Water-soluble phenylpyridazine compounds and compositions containing the same

ABSTRACT

Compounds having the formula (1):  
                 
 
     wherein R 1  represents an alkyl or alkenyl group, R 2  and R 3  each independently represents a hydrogen atom or an alkyl, hydroxyalkyl, dihydroxyalkyl or alkynyl group, or R 2  and R 3  may be fused together with the adjacent nitrogen atom to form a substituted or unsubstituted, nitrogen-containing, saturated heterocyclic group, X, Y and Z each independently represents a hydrogen atom, an alkyl group, a halogen atom or the like, and n stands for an integer of from 1 to 5; and also to pharmaceutical compositions containing them. These compounds have inhibitory activity against IL-1β production, high water solubility and good oral absorbability.

REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of a copending U.S.patent application Ser. No. 10/253,523 filed Sep. 25, 2002, which isincorporated herein by reference and which claims priority under 35 USC119(e) to provisional application Ser. No. 60/324,569 filed Sep. 26,2001, the teachings of which are hereby incorporated by reference hereinand priority to which is claimed herein.

FIELD OF THE INVENTION

[0002] This invention relates to water-soluble phenylpyridazinecompounds, which exhibit excellent inhibitory activity againstinterleukin-1β production, have high water solubility and oralabsorbability, and are useful for the prevention and treatment of immunesystem diseases, inflammatory diseases, and ischemic diseases, forexample, and also to compositions containing them as active ingredientstherein.

DESCRIPTION OF THE BACKGROUND

[0003] In many diseases, for example, rheumatism, arthritis,osteoporosis, inflammatory colitis, immune deficiency syndrome,ichorrhemia, hepatitis, nephritis, ischemic diseases, insulin-dependentdiabetes mellitus, arterial sclerosis, Parkinson's disease, Alzheimer'sdisease, and leukemia, for example, stimulation of interleukin-1βproduction, an inflammatory cytokine, is observed. This interleukin-1βserves to induce synthesis of an enzyme which is considered to take partin inflammation—like collagenase and PLA2—and, when intra-articularlyinjected to animals, causes multiarticular damage highly resemblingrheumatoid arthritis. In a healthy body, on the other hand, the activityof interleukin-1β is controlled by interleukin-1 receptor, solubleinterleukin-1 receptor and interleukin-1 receptor antagonist.

[0004] From research conducted using recombinant versions of thesebioactivity-inhibiting substances, anti-interleukin-1β antibodies andanti-receptor antibodies against various disease models and also fromresearch performed using knockout mice, interleukin-1β has been found toplay an important role in the body, leading to an increasing potentialof substances having interleukin-1β inhibitory activity as therapeuticsfor such diseases.

[0005] For example, immunosuppressors and steroids, which are used forthe treatment of rheumatism, have been reported to inhibit production ofinterleukin-1β. Among compounds currently under development, KE298, abenzoylpropionic acid compound [The Japanese Society of Inflammation(11th), 1990], for example, has been reported to exhibit inhibitoryactivity against interleukin-1β production although it is animmunoregulator. Inhibitory activity against interleukin-1β productionis also observed on a group of compounds which are called “COX-2selective inhibitors”, for example, nimesulide as a phenoxysulfonanilidecompound (DE 2333643), T-614 as a phenoxybenzopyran compound (U.S. Pat.No. 4,954,518), and tenidap (hydroxyindole compound) as a dual inhibitor(COX-1/5-LO).

[0006] Moreover, interleukin-1β production inhibitory activity is notthe primary action or effect of any of these compounds so the inhibitoryactivity against interleukin-1β production is less than the primaryaction thereof.

[0007] More recently, increased synthetic research has been conductedemphasizing inhibitory activity against interleukin-1β production.Production inhibitors can be classified into (1) a group of compoundswhich inhibit the transfer process of an inflammatory signal to a cellnucleus and (2) another group of compounds which inhibit the enzyme ICEthat functions in the processing of a precursor of interleukin-1β. Knownexamples of compounds presumed to have the former action (1) includeSB203580 [Japanese Language Laid-Open (Kokai) Publication (PCT) No. HEI7-503017], FR167653 (Eur. J. Pharm., 327, 169-175, 1997), E-5090 (EP376288), CGP47969A (Gastroenterology, 109, 812-828, 1995), hydroxyindolederivatives (Eur. J. Med. Chem. 31, 187-198, 1996), and triarylpyrrolederivatives (WO 9705878), while known examples of compounds presumed tohave the latter action (2) include VE-13,045 which is a peptide compound(Cytokine, 0.8 (5), 377-386, 1996)

[0008] None of these compounds, however, exhibit sufficient inhibitoryactivity against interleukin-1β production.

[0009] On the other hand, it is known that 5,6-diphenyl-pyridazinecompounds exhibit analgesic and anti-inflammatory action (Eur. J. Med.Chem., 14, 53-60, 1979). Further, 6-phenylpyridazinones have beenreported to be useful as cardio-active compounds (U.S. Pat. No.4,404,203). Nothing has been reported, however, with respect toinhibitory activity of these pyridazine compounds against interleukin-1βproduction.

[0010] The present inventors previously reported in WO 99/44995 thathigh inhibitory activity against interleukin-1β production was observedon phenylpyridazine compounds. Recently, certain phenylpyridazinecompounds having inhibitory activity against interleukin-1β productionhave been reported (JP 7-69894 A, WO 98/41511, WO 99/10331, WO 99/10332,WO 99/25697, WO 00/50408). These reported compounds, however, aredifferent in chemical structure from the compounds of the presentinvention.

SUMMARY OF THE INVENTION

[0011] The compounds disclosed in WO 99/44995 exhibit strong inhibitoryactivity against interleukin-1β production. However, the watersolubility of these compounds is so low that their formulation intopharmaceutical preparations, such as tablets, was practicallyimpossible. In the course of a further investigation, however, thepresent inventors discovered that the introduction of a substituted orunsubstituted aminoalkyl group to the 4-position of6-phenylpyridazine-3-one affords a compound useful as a preventive ortherapeutic for immune system diseases, inflammatory diseases, andischemic diseases, for example, due to its significantly improved watersolubility, good oral absorbability and excellent inhibitory activityagainst interleukin-1β production, leading to the completion of thepresent invention.

[0012] Thus, in one aspect of the present invention, there is provided apheylpyridazine compound represented by the following formula (1):

[0013] wherein:

[0014] R¹ represents a substituted or unsubstituted alkyl group or asubstituted or unsubstituted alkenyl group;

[0015] R² and R³ each independently represents a hydrogen atom or analkyl, hydroxyalkyl, dihydroxyalkyl or alkynyl group, or R² and R³ maybe fused together with the adjacent nitrogen atom to form a substitutedor unsubstituted, nitrogen-containing, saturated heterocyclic group;

[0016] X, Y and Z each independently represents a hydrogen or halogenatom, a substituted or unsubstituted alkyl, alkoxy, alkylthio,alkylsulfinyl or alkylsulfonyl group, or a substituted or unsubstitutedaryl group; and

[0017] n stands for a number of from 1 to 5;

[0018] with the proviso that R² and R³ are not hydrogen atoms or thesame C₁-C₃ alkyl groups at the same time when R is a benzyl group or aC₁-C₃ alkyl group; or a salt thereof.

[0019] In another aspect of the present invention, there is alsoprovided a medicine comprising the phenylpyridazine compound (1) or thesalt thereof as an active ingredient.

[0020] In yet a further aspect of the present invention, there is alsoprovided a pharmaceutical composition comprising the phenylpyridazinecompound (1) or the salt thereof and a pharmacologically acceptablecarrier.

[0021] In still a further aspect of the present invention, there is alsoprovided use of the phenylpyridazine compound (1) or the salt thereoffor the production of a medicine.

[0022] In a yet further aspect of the present invention, there is alsoprovided a method for treating a disease caused by stimulation ofinterleukin-1β production, which comprises administering thephenylpyridazine compound (1) or the salt thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0023]FIG. 1 is a graphic representation of the oral absorbability of acompound according to the present invention (Example 83) and acomparative compound 3;

[0024]FIG. 2 is graphic representations of the oral absorbability ofanother compound according to the present invention (Example 23);

[0025]FIG. 3 is graphic representations of the oral absorbability of afurther compound according to the present invention (Example 25);

[0026]FIG. 4 is graphic representations of the oral absorbability of astill further compound according to the present invention (Example 143).

[0027]FIG. 5 is graphic representations of the oral absorbability of yetfurther compounds according to the present invention (Examples 245 and246); and

[0028]FIG. 6 is graphic representations of the oral absorbability ofstill yet further compounds according to the present invention (Examples193, 247, 248 and 249).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] In the above formula (1), the alkyl moieties in the alkyl,hydroxyalkyl, dihydroxyalkyl, alkoxy, alkylthio, alkyl-sulfinyl andalkylsulfonyl groups represent those having 1 to about 12 carbon atoms,more preferably 1 to 7 carbon atoms. These alkyl moieties may includelinear, branched and cyclic alkyl groups as well as alkyl groups havingcyclic structures, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyland cyclohexylmethyl.

[0030] In the above formula (1), the alkyl group represented by R¹ haspreferably 1 to about 12 carbon atoms, more preferably 1 to 7 carbonatoms, notably 4 to 7 carbon atoms. Illustrative of such alkyl groupsare linear, branched and cyclic alkyl groups as well as alkyl groupshaving cyclic structures. Preferred examples can include methyl, ethyl,propyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyland cyclohexylmethyl, with methyl, ethyl, isobutyl, cyclopropylmethyland cyclopentylmethyl being particularly preferred.

[0031] The alkenyl group represented by R¹ preferably has 2 to about 12carbon atoms, with 2 to 7 carbon atoms being particularly preferred.Illustrative of such alkenyl groups are linear and branched alkenylgroups, specifically vinyl, propenyl, butenyl and pentenyl.

[0032] Illustrative of group(s) which the alkyl or alkenyl grouprepresented by R¹ may contain as substituent (s) are substituted orunsubstituted aryl groups and substituted or unsubstituted heteroarylgroups. Examples of the aryl groups include aryl groups having 6 to 14carbon atoms, specifically phenyl and naphthyl, with phenyl beingparticularly preferred. Examples of the heteroaryl groups, on the otherhand, include 5- or 6-membered heteroaryl groups having 1 to 3 nitrogenatoms, specifically pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl,pyrazinyl and pyridazinyl, with pyridyl being particularly preferred.

[0033] These aryl or heteroaryl groups may contain 1 to 3 substituentssuch as halogen atoms, alkyl groups or alkoxy groups. Examples of thehalogen atoms include fluorine, chlorine, bromine and iodine, withfluorine and chlorine being particularly preferred. These alkyl andalkoxy groups preferably have 1 to 12 carbon atoms, with 1 to 7 carbonatoms being particularly preferred.

[0034] The alkyl, hydroxyalkyl and dihydroxyalkyl groups represented byR² and R³ preferably have 1 to 12 carbon atoms, with 1 to 7 carbon atomsbeing particularly preferred. These groups may preferably be linear orbranched. Specific examples include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, hydroxyethyl, hydroxypropyl, hydroxybutyl,dihydroxypropyl and dihydroxybutyl.

[0035] The alkynyl groups represented by R² and R³ preferably have 3 to12 carbon atoms, with 3 to 7 carbon atoms being particularly preferred.Illustrative is propargyl (2-propynyl).

[0036] Illustrative of the nitrogen-containing, saturated heterocyclicgroup which may be formed as a result of fusing R² and R³ with theadjacent nitrogen atom are 5- to 7-membered saturated heterocyclicgroups, specifically pyrrolidinyl, piperidino, piperazinyl,homopiperazinyl and morpholino, with piperazinyl, piperidino andmorpholino being particularly preferred.

[0037] Illustrative of group(s) which these heterocyclic groups maycontain as substituent (s) are halogen atoms, alkyl groups,alkoxycarbonyl groups and aralkyl groups. Examples of the halogen atomsinclude fluorine, chlorine, bromine and iodine. The alkyl groups cancontain 1 to 12 carbon atoms, preferably 1 to 7 carbon atoms.Illustrative of the alkoxycarbonyl groups are C₁-C₁₂ alkyloxycarbonylgroups, with C₁-C₇ alkyloxycarbonyl groups being preferred. Illustrativeof the aralkyl groups are phenyl(C₁-C₇ alkyl) groups, with benzyl beingparticularly preferred.

[0038] Illustrative of the halogen atoms represented by X, Y and Z arefluorine, chlorine, bromine, and iodine. The alkyl groups can contain 1to 12 carbon atoms, with 1 to 7 carbon atoms being particularlypreferred. Among these alkyl groups, linear or branched ones areparticularly preferred. Illustrative of group(s) which the alkyl groupmay contain as substituent(s) are halogen atoms and alkoxy groups. Thealkoxy, alkylthio, alkylsulfinyl and alkylsulfonyl groups can contain 1to 12 carbon atoms, with 1 to 7 carbon atoms being particularlypreferred. Among these alkoxy, alkylthio, alkylsulfinyl andalkylsulfonyl groups, linear or branched ones are particularlypreferred. Specific examples include methoxy, ethoxy, propoxy,isopropoxy, butoxy, methylthio, ethylthio, propylthio, isopropylthio,butylthio, methylsulfinyl, ethylsulfinyl, propylsulfinyl,isopropylsulfinyl, butylsulfinyl, methyl-sulfonyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, and butylsulfonyl. Illustrative ofthe aryl group are aryl groups having 6 to 14 carbon atoms, specificallyphenyl and naphthyl, with phenyl being particularly preferred.Illustrative of group(s) which the aryl group may contain assubstituent(s) are halogen atoms, alkyl groups, and alkoxy groups.

[0039] n stands for a number of from 1 to 5, with 1 to 3 being morepreferred, and with 1 or 3 being particularly preferred.

[0040] When R¹ is a benzyl group or a C₁-C₃ alkyl group, R² and R³ arenot hydrogen atoms or the same C₁-C₃ alkyl groups at the same time.

[0041] In the formula (1), particularly preferred as R¹ are isobutyl,cyclopropylmethyl, cyclopentylmethyl, cinnamyl, halogenocinnamyl,benzyl, halogenobenzyl, dihalogenobenzyl, (halogenophenyl) ethyl,(dihalogenophenyl) ethyl, (halogenophenyl)propyl, and(dihalogenophenyl)propyl. Particularly preferred, specific examples caninclude chlorobenzyl, dichlorobenzyl, fluorobenzyl, difluorobenzyl,(chlorophenyl)ethyl, (dichlorophenyl)ethyl, (fluorophenyl)ethyl,(difluorophenyl)ethyl, (chlorophenyl)propyl, (dichlorophenyl)propyl,(fluorophenyl)propyl, and (difluorophenyl)propyl. Preferred as R² and R³are hydrogen, C₁₇ alkyl, C₁₇ hydroxyalkyl, and propargyl. Preferred asthe heterocyclic group formed by R² and R³ are piperazinyl, piperidino,pyrrolidinyl and morpholino, each of which may optionally be substitutedby one or more C₁₇ alkyl or benzyl groups. Preferred as X are methyl,methoxy, methylthio, and halogens. Preferred as Y are hydrogen, methyland halogens. Preferred as Z is hydrogen. Preferred as n are 1 and 3.

[0042] More preferred in the present invention are compounds each ofwhich is represented by the formula (1) wherein R¹ is a group selectedfrom halogenobenzyl, dihalogenobenzyl, (halogenophenyl) ethyl,(dihalogenophenyl) ethyl, (halogenophenyl)propyl or(dihalogenophenyl)propyl; R²(R³)N— is a group selected from amino,dimethylamino, piperazinyl or N-methylpiperazinyl; X is halogen ormethoxy; Y is methyl or halogen; Z is hydrogen; and n is 1 or 3.

[0043] Particularly prerferred in the present invention are compoundseach of which is represented by the formula (1) wherein R¹ is a groupselected from chlorobenzyl, dichlorobenzyl, fluorobenzyl,difluorobenzyl, (chlorophenyl) ethyl, (dichlorophenyl) ethyl,(chlorophenyl)propyl or (dichlorophenyl)propyl; R²(R³)N— is a groupselected from amino, dimethylamino, piperazinyl or N-methylpiperazinyl;X is halogen or methoxy; Y is methyl or halogen; Z is hydrogen; and n is1 or 3.

[0044] Specifically, the following compounds are preferred:

[0045] 4-dimethylaminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,

[0046] 2-cyclopropylmethyl-4-dimethylamino-methyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0047] 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-benzyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0048] 2-cyclopropyl-methyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)-methyl-2H-pyridazin-3-one,

[0049]4-N,N-bis(2-hydroxyethyl)amino-methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0050] 4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0051] 4-dimethyl-aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one,

[0052] 4-diethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one,

[0053] 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,

[0054] 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0055] 4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,

[0056]4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one,

[0057] 2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0058]2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,

[0059]4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropyl-methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,

[0060]2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one,

[0061]2-isobutyl-6-[4-(methylthio)-phenyl]-4-propargylaminomethyl-2H-pyridazin-3-one,

[0062]4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,

[0063] 2-(4-chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0064] 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0065] 2-cyclopentylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0066] 2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,

[0067] 4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0068]2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0069] 4-dimethylaminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0070] 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,

[0071] 4-aminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0072] 4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0073] 2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0074]2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0075]6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0076]4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,

[0077] 4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,

[0078]6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,

[0079] 4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,

[0080] 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one,

[0081] 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0082] 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one,

[0083]2-cyclopropylmethyl-4-(3-dimethylaminopropyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0084] 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one, and

[0085] 4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one.

[0086] Other preferred specific examples can include the followingcompounds:

[0087] 2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0088] 2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0089] 2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0090] 2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0091] 2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0092]2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one,

[0093] 4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,

[0094] 2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0095] 2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0096]2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0097]2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,

[0098] 4-aminomethyl-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,

[0099] 2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[0100]2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0101] 4-aminomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,

[0102] 2-(4-fluorobenzyl)-6(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one,

[0103] 2-(4-fluorobenzyl)-6(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,

[0104] 2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0105] 2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0106] 4-aminomethyl-2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0107] 4-aminomethyl-2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0108]2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,

[0109] 4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0110]2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0111]2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,

[0112]2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0113] 2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0114]2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0115]2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one,

[0116] 4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0117] 4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one, and

[0118]2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one.

[0119] Especially, the following compounds are preferred:

[0120] 2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0121]2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0122] 4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,

[0123]2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0124] 2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0125]2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0126]2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0127] 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,

[0128] 4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0129]2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0130] 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,

[0131] 2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0132]2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0133] 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0134] 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one,

[0135]4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,

[0136] 4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one, and

[0137] 2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one.

[0138] Of these, the following compounds are most preferred:

[0139] 2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,

[0140] 2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0141] 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,

[0142]2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,

[0143] 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one, or

[0144] 2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one, or a salt thereof.

[0145] As the salt of the compound (1) of the present invention, an acidaddition salt is preferred. Examples of the acid addition salt includeinorganic acid salts, such as the hydrochloride, sulfate, nitrate andphosphate, and organic acid salts, such as the methanesulfonate,maleate, fumarate, citrate and oxalate.

[0146] Further, the compound according to the present invention mayexist in the form of solvates and a keto-enol tautomer. Such solvatesand tautomer are encompassed by the present invention. Illustrative ofsolvates are those formed as a result of addition of solvents used uponproduction, for example, water and alcohols. No particular limitation isimposed on the solvents insofar as they do not adversely affect theinhibitory activity or the like of the compound according to the presentinvention against interleukin-1 production. As a solvate, the hydrate ispreferred.

[0147] The phenylpyridazine compound (1) according to the presentinvention can be prepared, for example, by the following preparationprocesses (a) to (d).

[0148] (a) Preparation Process of Compounds Having the Formula (1) inWhich n=1

[0149] wherein R⁴ represents an alkyl group, Hal represents a halogenatom, Ms represents a methanesulfonyl group, and R¹, R², R³, X, Y and Zhave the same meanings as described above.

[0150] A description will hereinafter be made about the individualreaction steps.

[0151] In the steps from an acetophenone (2) to a compound (5), theacetophenone (2) and diethyl ketomalonate are heated under stirring toyield a compound (3). Hydrazine is caused to act on the compound tocarry out a ring-closing reaction, and the reaction product is thentreated with an alkali, for example, sodium hydroxide or the like toafford a compound (4). The compound (4) is next reacted with an alcoholsuch as methanol to give the compound (5).

[0152] R¹-Hal is reacted to the compound (5) in the presence of analkali such as potassium carbonate to provide a compound (6). Thecompound (6) is hydrolyzed into a compound (7). After ethylchlorocarbonate is caused to act on the compound (7) to convert it intoan acid anhydride, the acid anhydride is reduced with a reducing agentsuch as sodium borohydride to afford a compound (8). A reaction ofmethanesulfonyl chloride with the compound (8) in the presence of a basesuch as triethylamine provides a compound (9), a key intermediate inthis reaction scheme.

[0153] A reaction of a desired amine (R²(R³)NH) with the compound (9)yields the target compound (1a). It is preferred to carry out thisreaction, for example, in a polar solvent such as dimethylformamide inthe presence or absence of an alkali such as potassium carbonate.Incidentally, if an amino group is contained in the group R² or R³ inthe amine, a reaction may be carried out using a raw material protectedwith an appropriate protecting group, for example, an alkoxycarbonylgroup, followed by the removal of the protecting group.

[0154] To obtain a compound (1a) in which R² and R³ are hydrogen atoms,potassium phthalimide is reacted with the compound (9), and the reactionproduct is reacted further with hydrazine or the like.

[0155] A compound (1a) in which X, Y and/or Z is a methylsulfinyl groupor a methylsulfonyl group can be obtained by oxidizing a correspondingcompound, in which X, Y and/or Z is a methylthio group, with a peracid,for example, perbenzoic acid. This methylsulfination ormethylsulfonation may be carried out at the stage of the intermediate(9).

[0156] (b) Preparation Process of Compounds Having the Formula (1) inWhich n=3

[0157] wherein Hal, Ms, R¹, R², R³, X, Y and Z have the same meanings asdefined above.

[0158] According to the preparation process (b), a carbon tetrahalidesuch as carbon tetrabromide is firstly reacted with the compound (8) inthe presence of triphenylphosphine to obtain a halogen derivative (10),with which a malonate is then reacted in the presence of sodium hydrideto yield a compound (11). An acid such as trifluoroacetic acid isreacted with the compound (11) to convert it into a dicarboxylic acid,followed by heating to yield a compound (12). Ethyl chlorocarbonate iscaused to act on the compound (12) to convert it into an acid anhydride,which is then reduced with a reducing agent such as sodium borohydrideto yield a compound (13). Methanesulfonyl chloride is reacted with thecompound (13) in the presence of a base such as triethylamine to yield acompound (14), a key intermediate in the process according to thepresent invention.

[0159] A target compound (1b) can be obtained by reacting acorresponding amine (R²R³NH) with the compound (14). This reaction maypreferably be conducted, for example, in the presence or absence of analkali such as potassium carbonate in a polar solvent such asdimethylformamide. When an amino group is contained in the group R² orR³ of the amine, a reaction may be conducted using a raw material inwhich the amino group has been protected with an appropriate protectinggroup (for example, an alkoxycarbonyl group), followed by deprotectionof the protecting group.

[0160] To yield a compound (1b) in which R² and R³ are both hydrogenatoms, the compound can be obtained by reacting potassium phthalimidewith the compound (14) and then reacting hydrazine or the like.

[0161] (c) Preparation Process of Compounds Having the Formula (1) inWhich n=2

[0162] wherein M represents a metal atom, and Hal, Ms, R¹, R², R³, X, Yand Z have the same meanings as defined above.

[0163] According to the preparation process (c), a cyanide such assodium cyanide is reacted with a halogen derivative (10) to convert itinto a nitrile derivative (15), which is then hydrolyzed to yield acompound (16). From the compound (16), a target compound (1c) can beobtained via an alcohol derivative (17) and a mesyloxy derivative (18)by a similar procedure as in the preparation of compounds each of whichcontains three methylene groups.

[0164] (d) Preparation Process of Compounds Having the Formula (1) inWhich n=4 or 5

[0165] These compounds can be obtained by combining the synthesisprocesses (b) and (c).

[0166] The salt of the compound (1) according to the present inventioncan be obtained by causing an organic acid or inorganic acid to act in amanner known per se in the art.

[0167] The compound (1) according to the present invention can beisolated and purified by subjecting it to purification procedurescommonly employed in organic synthesis chemistry, for example,filtration, extraction, washing, drying, concentration,recrystallization, various chromatographic procedures, and/or the like.Each intermediate can be subjected to the subsequent reaction withoutbothering to purify it. The compound (1) may be provided as a solvatewith a solvent such as a reaction solvent or recrystallization solvent,especially as the hydrate.

[0168] The compound (1) according to the present invention is excellentin water solubility, is also good in oral absorbability and hasinhibitory activity against interleukin-1β production, and therefore, isuseful as a preventive or therapeutic for immune system diseases,inflammatory diseases, ischemic diseases, osteoporosis, ichoremia andthe like. Examples of ischemic diseases include ischemic heart diseases,ischemic encephalopathy, ischemic nephritis, and ischemic hepatitis.

[0169] The pharmaceutical composition of the present invention containsthe compound (1) or the salt thereof as an active ingredient. Using theactive ingredient alone or together with a pharmacologically acceptablecarrier such as a solubilizer, excipient, binder or extender, it can beformed into pharmaceutical preparation forms such as tablets, capsules,granules, powders, injections and suppositories. These pharmaceuticalpreparations can be produced by known methods. For example, oralpreparations can be produced by suitably formulating the compound (1) orthe salt in combination with solubilizers such as tragacanth gum, gumarabic, sucrose esters, lecithin, olive oil, soybean oil and PEG400;excipients such as starch, mannitol and lactose; binders such ascarboxy-methylcellulose sodium and hydroxypropylcellulose;disintegrators such as crystalline cellulose and carboxy-methylcellulosecalcium; lubricants such as talc and magnesium stearate; anticakingagents such as light anhydrous silicic acid. The pharmaceuticalcomposition according to the present invention is administered orally orparenterally.

[0170] The administered dosage of the pharmaceutical compositionaccording to the present invention varies depending on the body weight,age, sex, conditions and the like of each patient. In general, however,it is preferred to administer to an adult in an amount of about 0.01 to1,000 mg, preferably 0.1 to 100 mg, of the present pharmaceuticalcomposition in terms of the compound (1) per day in 1 to 3 portions.

EXAMPLES

[0171] The present invention will now be further described by referenceto the following Examples. The Examples are provided solely for purposesof illustration and are not intended to be limitative.

Example 1

[0172] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

[0173] 1) Preparation of 4-(1-hydroxyethyl)-2-fluorotoluene

[0174] To an ice-cold solution of 3-fluoro-4-methylbenzaldehyde (50 mg,0.36 mmol) in THF (0.5 mL) was added dropwise a 0.93 M solution (0.47mL) of methylmagnesium bromide (0.44 mmol) in THF. The temperature ofthe reaction mixture was allowed to rise back to room temperature, atwhich the reaction mixture was stirred for 1 hour. Then, 2 mol/Lhydrochloric acid was added, and the mixture was extracted with ethylacetate. The extract was washed with brine and dried over anhydroussodium sulfate. The solvent was distilled off under reduced pressure toyield title compound as a pale yellow oil (55.8 mg, quantitative).

[0175]¹H NMR (400 MHz, CDCl₃) δ: 1.46 (3H, d, J=6.4 Hz), 2.26 (3H, d,J=1.8 Hz), 4.85 (1H, q, J=6.4 Hz), 6.99-7.06 (2H, m), 7.14 (1H, dd,J=7.8, 7.8 Hz).

[0176] 2) Preparation of 3′-fluoro-4′-methylacetophenone

[0177] To a solution of 4-(1-hydroxyethyl)-2-fluorotoluene (55.8 mg,0.36 mmol) in methylene chloride (1 mL) were added molecular sieve 4A(56.0 mg) and PCC 94.0 mg (0.43 mmol), and the mixture was stirred atroom temperature for 1 hour. The reaction mixture was filtered throughCelite, and the filtrate was concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to yield thetitle compound as a pale yellow oil (47.5 mg, 86.0%).

[0178]¹H NMR (400 MHz, CDCl₃) δ: 2.32 (3H, d, J=1.8 Hz), 2.56 (3H, s),7.26 (1H, dd, J=7.6, 7.6 Hz), 7.56 (1H, dd, J=1.6, 10.4 Hz), 7.62 (1H,dd, J=1.6, 7.8 Hz).

[0179] 3) Preparation of ethyl2-ethoxycarbonyl-4-(3-fluoro-4-methylphenyl)-2-hydroxy-4-oxobutanoate

[0180] A mixture of 3′-fluoro-4′-methylacetophenone (4.92 g, 32.3 mmol)and diethyl ketomalonate (6.19 g, 35.6 mmol) was stirred at 120° C. for48 hours. The temperature of the reaction mixture was allowed to dropback to room temperature, and the mixture was purified by columnchromatography on silica gel [silica gel 100 g, chloroform/ethyl acetate(10/1)] to yield the title compound as yellow crystals (8.41 g, 79.3%).

[0181] Melting point: 68.7-69.0° C.

[0182]¹H NMR (400 MHz, CDCl₃) δ: 1.30 (6H, t, J=7.1 Hz), 2.34 (3H, s),3.78 (2H, s), 4.25 (1H, s), 4.31 (4H, q, J=7.1 Hz), 7.29 (1H, dd, J=7.6Hz), 7.59 (1H, d, J=10.2 Hz), 7.65 (1H, dd, J=1.5, 7.8 Hz).

[0183] IR (KBr) cm⁻¹: 3485, 1740, 1684, 1253, 856, 577.

[0184] 4) Preparation of4-carboxy-6-(3-fluoro-4-methylphenyl)-2H-pyridazin-3-on e

[0185] To a solution of ethyl2-ethoxycarbonyl-4-(3-fluoro-4-methylphenyl)-2-hydroxy-4-ox obutanoate(8.41 g, 25.8 mmol) inisopropanol (100 mL) was added hydrazinemonohydrate (2.84 g, 56.8 mmol), and the mixture was heated understirring at 100° C. for 6 hours. Then, 2 mol/L sodium hydroxide wasadded, and the mixture was stirred further at the same temperature for 4hours. The reaction mixture was ice-cooled, and concentratedhydrochloric acid was added to acidify the system. The precipitate wascollected by filtration, thoroughly washed with water and dried to yieldthe title compound as a slightly yellow crystalline powder (5.67 g,87.7%).

[0186] Melting point: 281.3-282.0° C. (dec.)

[0187]¹H NMR (400 MHz, DMSO-d₆) δ: 2.28 (3H, d, J=1.0 Hz), 7.41 (1H, dd,J=8.1, 8.1 Hz), 7.67-7.73 (2H, m), 8.49 (1H, s), 14.09 (1H, br).

[0188] IR (KBr) cm⁻¹: 1736, 1641, 1441, 1125, 926, 806.

[0189] 5) Preparation of6-(3-fluoro-4-methylphenyl)-4-methoxy-carbonyl-2H-pyrid azin-3-one

[0190] To an ice-cold suspension of4-carboxy-6-(3-fluoro-4-methyl-phenyl)-2H-pyridazin-3-one (5.50 g, 22.2mmol) in methanol (100 mL) was added dropwise thionyl chloride (2.72 g,24.4 mmol), and the mixture was stirred at 80° C. for 8 hours. Thetemperature of the reaction mixture was allowed to drop back to roomtemperature, and the solvent was distilled off under reduced pressure.Water was added to the ice-cold residue. The precipitate was collectedby filtration, washed with water and dried to yield the title compoundas pale yellow fine-needles (5.43 g, 92.7%).

[0191] Melting point: 206.0-207.3° C.

[0192]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, d, J=1.7 Hz), 4.00 (3H, s),7.29 (1H, dd, J=7.9, 7.9 Hz), 7.46-7.53 (2H, m), 8.32 (1H, s), 11.61(1H, s).

[0193] IR (KBr) cm⁻¹: 1715, 1671, 1266, 1177, 1091, 812.

[0194] 6) Preparation of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

[0195] To a solution of6-(3-fluoro-4-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one (5.28g, 20.0 mmol) in N,N-dimethylformamide (40 mL) were added potassiumcarbonate (5.53 g, 40.0 mmol) and isobutyl bromide (3.29 g, 24.0 mmol),and the mixture was stirred at 80° C. for 1 hour. The temperature of thereaction mixture was allowed to drop back to room temperature. Asaturated aqueous solution of sodium hydrogencarbonate was added, andthe mixture was extracted with ethyl acetate. The extract was washedwith brine, and dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified by columnchromatography on silica gel [silica gel 100 g, chloroform/methanol(100/1→50/1)) to yield the title compound as an orange oil (5.41 g,84.9%).

[0196]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.32-2.42 (1H,m), 2.33 (3H, s), 3.98 (3H, s), 4.12 (2H, d, J=7.4 Hz), 7.28 (1H, dd,J=7.8, 7.8 Hz), 7.46 (1H, dd, J=1.6, 7.8 Hz), 7.50 (1H, dd, J=1.6, 10.7Hz), 8.21 (1H, s).

[0197] 7) Preparation of4-carboxy-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyr idazin-3-one

[0198] To a suspension of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one(5.27 g, 16.6 mmol) in methanol (50 mL) was added a 2 mol/L aqueoussodium hydroxide (50 mL), and the mixture was stirred at 60° C. for 15minutes. The temperature of the reaction mixture was allowed to dropback to room temperature, and then, water was added. After the systemwas acidified with concentrated hydrochloric acid, the mixture wasextracted with ethyl acetate. The extract was washed with brine, anddried over anhydrous sodium sulfate. The solvent was distilled off underreduced pressure, and the residue was recrystallized fromchloroform-hexane to yield the title compound as colorless fine-needles(4.73 g, 93.8%).

[0199] Melting point: 159.0-159.5° C.

[0200]¹H NMR (400 MHz, CDCl₃) δ: 1.02 (6H, d, J=6.7 Hz), 2.33-2.42 (1H,m), 2.35 (3H, d, J=1.6 Hz), 4.21 (2H, d, J=7.4 Hz), 7.32 (1H, dd, J=7.8,7.8 Hz), 7.52 (1H, dd, J=1.8, 8.0 Hz), 7.55 (1H, dd, J=1.8, 10.6 Hz),8.63 (1H, s), 14.13 (1H, s).

[0201] IR (KBr) cm⁻¹: 2960, 1742, 1633, 1574, 1425, 1101, 820.

[0202] 8) Preparation of6-(3-fluoro-4-methylphenyl)-4-hydroxy-methyl-2-isobutyl-2H-pyridazin-3-one

[0203] To a solution of4-carboxy-6-(3-fluoro-4-methyl-phenyl)-2-isobutyl-2H-pyrida zin-3-one(4.53 g, 14.9 mmol) in THF (40 mL) was added triethylamine (1.66 g, 16.4mmol). To the ice-cooled mixture was added dropwise a solution of ethylchlorocarbonate (1.78 g, 16.4 mmol) in THF (5 mL), and the mixture wasstirred for 30 minutes. Triethylamine hydrochloride was filtered off. Asolution of sodium borohydride (564 mg, 14.9 mmol) in water (1 mL) wasadded to the filtrate, and then, the mixture was stirred at roomtemperature for 10 minutes. Thereafter, 2 mol/L hydrochloric acid wasadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with brine, and dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure. The residue was purified by column chromatography on silicagel [silica gel 300 g, chloroform/methanol (100/1→50/1)) to yield thetitle compound as a colorless crystalline powder (1.08 g, 25.0%).

[0204] Melting point: 147.3-147.5° C.

[0205]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.29-2.39 (1H,m), 2.32 (3H, d, J=10.8 Hz), 3.05 (1H, t, J=6.0 Hz), 4.08 (2H, d, J=7.4Hz), 4.71 (2H, dd, J=1.2, 6.0 Hz), 7.26 (1H, dd, J=7.8 Hz), 7.46 (1H,dd, J=7.8, 7.8 Hz), 7.50 (1H, dd, J=1.8, 10.8 Hz), 7.65 (1H, s).

[0206] IR (KBr) cm⁻¹: 3330, 1644, 1596, 1514, 1226, 1087, 824.

[0207] 9) Preparation of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[0208] To an ice-cold solution of6-(3-fluoro-4-methyl-phenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one(1.08 g, 3.73 mmol) in methylene chloride (20 mL) were addedtriethylamine (491 mg, 4.85 mmol) and methanesulfonyl chloride (513 mg,4.48 mmol), and the mixture was stirred for 1 hour. A saturated aqueoussolution of sodium hydrogencarbonate was added to the reaction mixture,and then, the mixture was extracted with ethyl acetate. The extract waswashed with brine and dried over anhydrous sodium sulfate. The solventwas distilled off under reduced pressure, and the residue wasrecrystallized from chloroform-hexane to yield the title compound as acolorless crystalline powder (964 mg, 70.4%).

[0209] Melting point: 142.7-143.4° C.

[0210]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.30-2.34 (1H,m), 2.33 (3H, d, J=10.8 Hz), 3.17 (3H, s), 4.08 (2H, d, J=7.4 Hz), 5.27(2H, d, J=1.4 Hz), 7.27 (1H, dd, J=7.8, 7.8 Hz), 7.45 (1H, dd, J=1.8,8.0 Hz), 7.50 (1H, dd, J=1.8, 10.9 Hz), 7.76 (1H, t, J=1.4 Hz).

[0211] IR (KBr) cm⁻¹: 3435, 2964, 1658, 1610, 1354, 1165, 875.

[0212] 10) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

[0213] To a solution of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one (100 mg, 0.27 mmol) in acetonitrile (1 mL)were added potassium carbonate (56.3 mg, 0.41 mmol) and tert-butyl1-piperazine-carboxylate (60.7 mg, 0.33 mmol), and the mixture wasstirred at 80° C. for 2 hours. The temperature of the reaction mixturewas allowed to drop back to room temperature, and then, water was added.The mixture was extracted with chloroform. The extract was dried overanhydrous sodium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by column chromatography onsilica gel [chloroform/methanol (40/1)] to yield the title compound as ayellow oil (115 mg, 92.4%).

[0214]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=3.4 Hz), 1.47 (9H, s),2.28-2.40 (1H, m), 2.33 (3H, s), 2.52 (4H, t, J=4.7 Hz), 3.51 (4H, t,J=4.7 Hz), 3.58 (2H, s), 4.07 (2H, d, 4.1 Hz), 7.27 (1H, dd, J=7.6, 7.6Hz), 7.44-7.52 (2H, m), 7.77 (1H, s).

Example 2

[0215] Preparation of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[0216] To a solution of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one(115 mg, 0.25 mmol) in ethyl acetate (2 mL) was added a 4 mol/L solution(2 mL) of hydrochloric acid in ethyl acetate, and the mixture wasstirred at 50° C. for 1 hour. The temperature of the reaction mixturewas allowed to drop back to room temperature, and then, diethyl etherwas added. The precipitate was collected to yield the title compound asa colorless crystalline powder (81.1 mg, 75.0%).

[0217] Melting point: 186.2-195.0° C. (dec.)

[0218]¹H NMR (400 MHz, DMSO-d₆) δ: 0.95 (6H, d, J=6.8 Hz), 2.22-2.33(1H, m), 2.29 (3H, d, J=2.0 Hz), 3.15 (4H, br), 3.32 (4H, t, J=5.2 Hz),3.93 (2H, s), 4.02 (2H, d, J=7.1 Hz), 7.40 (1H, dd, J=8.1, 8.1 Hz),7.59-7.66 (2H, m), 8.21 (1H, s).

[0219] IR (KBr) cm⁻¹: 1656, 1610, 1425, 1306, 956.

[0220] Mass m/z: 358 (M⁺)

Example 3

[0221] Preparation of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[0222] Following the procedure of Example 1 (10),6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 93.4%).

[0223]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.28-2.40 (1H,m), 2.33 (6H, s), 2.52 (4H, br), 2.62 (4H, br), 3.58 (2H, s), 4.07 (2H,d, J=7.4 Hz), 7.27 (1H, dd, J=7.9, 7.9 Hz), 7.46-7.52 (2H, m), 7.75 (1H,d, J=1.0 Hz).

Example 4

[0224] Preparation of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[0225] To a solution of6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one (94.4 mg, 0.25 mmol) in methanol (1 mL)was added dropwise at room temperature under stirring a 4 mol/L solution(0.15 mL) of hydrochloric acid in ethyl acetate. The solvent wasdistilled off under reduced pressure. The residue was recrystallizedfrom methanol-diethyl ether to yield the title compound as a colorlesscrystalline powder (71.9 mg, 63.7%).

[0226] Melting point: 248.5-252.0° C. (dec.)

[0227]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.8 Hz), 2.29 (3H, d,J=1.8 Hz), 2.22-2.33 (1H, m), 2.77 (3H, s), 3.18 (4H, br), 3.38 (4H,br), 3.91 (2H, s), 4.02 (2H, d, J=7.0 Hz), 7.40 (1H, dd, J=8.0, 8.0 Hz),7.59-7.65 (2H, m), 8.16 (1H, s).

[0228] IR (KBr) cm⁻¹: 1653, 1609, 1451, 1425, 951.

[0229] Mass m/z: 372 (M⁺)

Example 5

[0230] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

[0231] Following the procedure of Example 1 (10),6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 84.8%).

[0232]¹H NMR (400 MHz, CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 2.27-2.38 (1H,m), 2.30 (3H, s), 2.70 (4H, t, J=5.0 Hz), 3.66 (4H, t, J=5.2 Hz), 3.69(2H, s), 4.06 (2H, d, J=7.2 Hz), 7.23 (1H, dd, J=7.9, 7.9 Hz), 7.46-7.52(2H, m), 7.79 (1H, s).

Example 6

[0233] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one hydrochloride

[0234] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the titlecompound as a colorless crystalline powder (yield: 85.9%).

[0235] Melting point: 159.7-160.7° C.

[0236]¹H NMR (400 MHz, DMSO-d₆) δ: 0.96 (6H, d, J=6.6 Hz), 2.20-2.34(1H, m), 2.30 (3H, d, J=1.7 Hz), 3.35 (4H, t, J=5.1 Hz), 3.84 (4H, t,J=5.1 Hz), 4.05 (2H, d, J=7.0 Hz), 4.45 (2H, s), 7.42 (1H, dd, J=8.2,8.2 Hz), 7.62-7.68 (2H, m), 8.47 (1H, s).

[0237] IR (KBr) cm⁻¹: 1663, 1613, 1427, 1087, 1052, 821.

[0238] Mass m/z: 359 (M⁺-H₂O)

Example 7

[0239] Preparation of4-dimethylaminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

[0240] To 6-(3-fluoro-4-methylphenyl)-2-isobutyl-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one (100 mg, 0.27 mmol) was added a 40% aqueousdimethylamine (1 mL), and the mixture was stirred at 80° C. for 2 hours.The temperature of the reaction mixture was allowed to drop back to roomtemperature, and then, water was added. The mixture was extracted withchloroform. The extract was dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by column chromatography on silica gel [chloroform/methanol(40/1)] to yield the title compound as a yellow oil (69.7 mg, 80.9%).

[0241]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.23-2.41 (1H,m), 2.31 (3H, s), 2.35 (6H, s), 3.50 (2H, d, J=1.2 Hz), 4.08 (2H, d,J=7.4 Hz), 7.26 (1H, dd, J=7.9, 7.9 Hz), 7.47-7.54 (2H, m), 7.76 (1H, d,J=1.4 Hz).

Example 8

[0242] Preparation of4-dimethylaminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one hydrochloride

[0243] Following the procedure of Example 4,4-dimethyl-aminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the title compound as acolorless crystalline powder (yield: 85.4%).

[0244] Melting point: 246.5-248.5° C.

[0245]¹H NMR (400 MHz, DMSO-d₆) δ: 0.96 (6H, d, J=6.6 Hz), 2.23-2.34(1H, m), 2.30 (3H, s), 2.81 (6H, s), 4.05 (2H, d, J=7.0 Hz), 4.27 (2H,s), 7.41 (1H, dd, J=8.0, 8.0 Hz), 7.22-7.68 (2H, m), 8.52 (1H, s).

[0246] IR (KBr) cm⁻¹: 1648, 1607, 1422, 1227, 1110, 1051.

[0247] Mass m/z: 317 (M⁺)

Example 9

[0248] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[0249] 1) Preparation of4-carboxy-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[0250] Following the procedure of Example 1 (7),2-cyclo-propylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxy-carbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as yellow crystals (yield:98.9%).

[0251] Melting point: 169.1-170.7° C.

[0252]¹H NMR (400 MHz, CDCl₃) δ: 0.50-0.67 (4H, m), 1.40-1.50 (1H, m),3.97 (3H, s), 4.23 (2H, d, J=7.3 Hz), 7.07 (1H, dd, J=8.5, 8.5 Hz), 7.57(1H, ddd, J=1.2, 2.2, 8.5 Hz), 7.85 (1H, dd, J=2.2, 12.2 Hz), 8.63 (1H,s), 14.20 (1H, s).

[0253] IR (KBr) cm⁻¹: 1761, 1629, 1521, 1476, 1461.

[0254] Mass m/z: 318 (M⁺).

[0255] 2) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[0256] Following the procedure of Example 1 (8),4-carboxy-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow fine-needles(yield: 21.3%).

[0257] Melting point: 119.4-122.6° C.

[0258]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.60 (4H, m), 1.36-1.47 (1H, m),3.12 (1H, t, J=6.0 Hz), 3.95 (3H, s), 4.10 (2H, d, J=7.3 Hz), 4.72 (2H,dd, J=1.2, 5.9 Hz), 7.03 (1H, dd, J=8.5, 8.5 Hz), 7.51 (1H, ddd, J=1.2,2.2, 8.5 Hz), 7.62 (1H, dd, J=2.2, 12.4 Hz), 7.65 (1H, t, J=1.2 Hz).

[0259] IR (KBr) cm⁻¹: 3431, 1652, 1604, 1524.

[0260] Mass m/z: 304 (M⁺).

[0261] 3) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[0262] Following the procedure of Example 1 (9),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound asslightly yellow needles (yield: 80.4%).

[0263] Melting point: 156.9-158.4° C.

[0264]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.61 (4H, m), 1.36-1.46 (1H, m),3.18 (3H, s), 3.95 (3H, s), 4.10 (2H, d, J=7.3 Hz), 5.28 (2H, d, J=1.2Hz), 7.03 (1H, dd, J=8.5, 8.5 Hz), 7.51 (1H, ddd, J=1.2, 2.2, 8.5 Hz),7.62 (1H, dd, J=2.2, 12.2 Hz), 7.76 (1H, t, J=1.2 Hz).

[0265] IR (KBr) cm⁻¹: 1656, 1612, 1523, 1358, 1177.

[0266] Mass m/z: 382 (M⁺).

[0267] 4) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylaminomethyl-2H-pyridazin-3-one

[0268] A solution of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one (160 mg, 0.42 mmol) in 30%methylamine/ethanol (5 mL) was stirred at 80° C. for 4 hours in a sealedtube. The solvent was distilled off under reduced pressure, and theresidue was purified by preparative thin-layer chromatography on silicagel [developing solvent: chloroform/methanol (10/1)] to yield titlecompound as a slightly yellow oil (87 mg, 65.5%).

[0269]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.59 (4H, m), 1.36-1.47 (1H, m),1.85 (1H, br), 2.52 (3H, s), 3.80 (2H, d, J=1.2 Hz), 3.95 (3H, s), 4.10(2H, d, J=7.3 Hz), 7.01 (1H, dd, J=8.5, 8.5 Hz), 7.52 (1H, ddd, J=1.2,2.2, 8.5 Hz), 7.62 (1H, dd, J=2.2, 12.4 Hz), 7.66 (1H, t, J=1.2 Hz)

[0270] Mass m/z: 317 (M⁺).

Example 10

[0271] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methylaminomethyl-2H-pyridazin-3-one hydrochloride

[0272] Following the procedure of Example 4,2-cyclopropyl-methyl-6-(3-fluoro-4-methoxyphenyl)-4-methylaminomethyl-2H-pyridazin-3-one was reacted to yield the title compound asslightly yellow needles (yield: 93.8%).

[0273] Melting point: 220.8-224.3° C. (dec.)

[0274]¹H NMR (400 MHz, DMSO-d₆) δ: 0.44-0.54 (4H, m), 1.29-1.40 (1H, m),2.66 (3H, s), 3.91 (3H, s), 4.05 (2H, d, J=7.3 Hz), 4.12 (2H, s), 7.33(1H, dd, J=8.5, 8.5 Hz), 7.70-7.79 (2H, m), 8.39 (1H, s).

[0275] IR (KBr) cm⁻¹: 1645, 1599, 1521, 1437.

Example 11

[0276] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[0277] Following the procedure of Example 1 (10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 73.8%).

[0278]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.59 (4H, m), 1.36-1.47 (1H, m),2.33 (3H, s), 2.52 (4H, br), 2.62 (4H, br), 3.80 (2H, d, J=1.2 Hz), 3.58(2H, d, J=1.0 Hz), 3.95 (3H, s), 4.09 (2H, d, J=7.3 Hz), 7.04 (1H, dd,J=8.5, 8.5 Hz), 7.53 (1H, ddd, J=1.2, 2.2, 8.5 Hz), 7.61 (1H, dd, J=2.2,12.4 Hz), 7.74 (1H, t, J=1.2 Hz).

[0279] IR (Neat) cm⁻¹: 1652, 1608, 1520, 1456, 1440.

[0280] Mass m/z: 386 (M⁺)

Example 12

[0281] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[0282] Following the procedure of Example 4,2-cyclopropyl-methyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield thetitle compound as pale yellow needles (yield: 81.0%).

[0283] Melting point: 237.4-238.4° C. (dec.)

[0284]¹H NMR (400 MHz, DMSO-d₆) δ: 0.47-0.58 (4H, m), 1.31-1.41 (1H, m),2.33 (3H, s), 2.52 (4H, br), 2.62 (4H, br), 2.90-3.85 (10H, m), 3.91(3H, s), 4.03 (2H, d, J=7.3 Hz), 7.30 (1H, dd, J=8.5, 8.5 Hz), 7.70-7.78(2H, m) 8.28 (1H, brs).

[0285] IR (KBr) cm⁻¹: 1653, 1608, 1523, 1438.

Example 13

[0286] Preparation of2-cyclopropylmethyl-4-dimethylamino-methyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[0287] Following the procedure of Example 7,2-cyclopropyl-methyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxy-methyl-2H-pyridazin-3-one and dimethylamine were reacted toyield the title compound as a yellow oil (yield: 88.1%).

[0288]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.59 (4H, m), 1.37-1.48 (1H, m),2.36 (6H, s), 3.51 (2H, s), 3.95 (3H, s), 4.10 (2H, d, J=7.3 Hz), 7.02(1H, dd, J=8.5, 8.5 Hz), 7.53-7.57 (1H, m), 7.64 (1H, dd, J=2.2, 12.7Hz), 7.75 (1H, s).

[0289] IR (Neat) cm⁻¹: 1652, 1608, 1523, 1456, 1438.

[0290] Mass m/z: 331 (M⁺).

Example 14

[0291] Preparation of2-cyclopropylmethyl-4-dimethylamino-methyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one hydrochloride

[0292] Following the procedure of Example 4,2-cyclopropyl-methyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compoundas slightly yellow needles (yield: 89.0%).

[0293] Melting point: 233.6-235.0° C. (dec.)

[0294]¹H NMR (400 MHz, DMSO-d₆) δ: 0.41-0.54 (4H, m), 1.27-1.37 (1H, m),2.83 (6H, s), 3.92 (3H, s), 4.06 (2H, d, J=7.3 Hz), 4.30 (2H, s), 7.33(1H, dd, J=8.8, 8.8 Hz), 7.69-7.77 (2H, m), 8.51 (1H, s).

[0295] IR (KBr) cm⁻¹: 1648, 1584, 1522, 1439.

Example 15

[0296] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(2-hydroxyethyl)aminomethyl-2H-pyridazin-3-one

[0297] Following the procedure of Example 9 (4),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-oneand 2-aminoethanol were reacted to yield the title compound as a yellowoil (yield: 72.1%).

[0298]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.59 (4H, m), 1.36-1.47 (1H, m),2.86 (2H, t, J=5.1 Hz), 3.73 (2H, t, J=5.1 Hz), 3.84 (2H, d, J=1.0 Hz),3.94 (3H, s) 4.10 (2H, d, J=7.3 Hz), 7.02 (1H, dd, J=8.5, 8.5 Hz),7.50-7.54 (1H, m), 7.62 (1H, dd, J=2.2, 12.7 Hz), 7.67 (1H, s).

[0299] IR (Neat) cm⁻¹: 3411, 1651, 1605, 1523, 1439.

[0300] Mass m/z: 347 (M⁺).

Example 16

[0301] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(2-hydroxyethyl)aminomethyl-2H-pyridazin-3-onehydrochloride

[0302] Following the procedure of Example 4,2-cyclopropyl-methyl-6-(3-fluoro-4-methoxyphenyl)-4-N-(2-hydroxyethyl)-aminomethyl-2H-pyridazin-3-one was reacted to yield thetitle compound as pale brown needles (yield: 79.2%).

[0303] Melting point: 166.8-169.3° C. (dec.)

[0304]¹H NMR (400 MHz, CDCl₃) δ: 0.40-0.54 (4H, m), 1.27-1.37 (1H, m),3.13 (2H, br), 3.28 (2H, br), 3.74 (3H, s), 4.05 (2H, d, J=7.1 Hz), 4.18(2H, s), 5.31 (1H, br), 7.33 (1H, dd, J=8.8, 8.8 Hz), 7.69-7.79 (2H, m)8.40 (1H, s).

[0305] IR (KBr) cm⁻¹: 3334, 1654, 1616, 1604, 1523, 1441.

Example 17

[0306] Preparation of4-(4-benzyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[0307] Following the procedure of Example 1 (10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-oneand 1-benzylpiperazine were reacted to yield the title compound as ayellow oil (yield: 97.7%).

[0308]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.58 (4H, m), 1.36-1.46 (1H, m),2.56 (4H, br), 2.62 (4H, br), 3.56 (2H, s), 3.58 (2H, d, J=1.0 Hz), 3.95(3H, s), 4.09 (2H, d, J=7.1 Hz), 7.04 (1H, dd, J=8.5, 8.5 Hz), 7.23-7.36(5H, m), 7.50-7.55 (1H, m), 7.61 (1H, dd, J=2.2, 12.7 Hz), 7.75 (1H, s).

[0309] IR (Neat) cm⁻¹: 1652, 1608, 1522, 1438, 1289, 1237.

[0310] Mass m/z: 462 (M⁺).

Example 18

[0311] Preparation of4-(4-benzyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onedihydrochloride

[0312] Following the procedure of Example 4,4-(4-benzyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the titlecompound as slightly yellow prisms (yield: 85.7%).

[0313] Melting point: 253.0-257.9° C. (dec.)

[0314]¹H NMR (400 MHz, DMSO-d₆) δ: 0.41-0.55 (4H, m), 1.27-1.38 (1H, m),3.06-3.49 (10H, br), 3.56 (2H, s), 3.91 (3H, s), 4.02 (2H, d, J=7.3 Hz),4.39 (2H, brs), 7.30 (1H, dd, J=8.5, 8.5 Hz), 7.44-7.48 (3H, m),7.59-7.64 (2H, m), 7.69-7.77 (2H, m), 8.30 (1H, brs).

[0315] IR (KBr) cm⁻¹: 1656, 1616, 1523, 1439, 1292, 1271.

Example 19

[0316] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazi n-3-one

[0317] Following the procedure of Example 1 (10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a pale brown oil (yield: 98.9%).

[0318]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.59 (4H, m), 1.47 (9H, s),1.38-1.46 (1H, m), 2.53 (4H, t, J=4.9 Hz), 3.51 (4H, t, J=4.9 Hz), 3.58(2H, d, J=1.2 Hz), 3.95 (3H, s), 4.10 (2H, d, J=7.3 Hz), 7.03 (1H, dd,J=8.5, 8.5 Hz), 7.51 (1H, ddd, J=1.2, 2.2, 8.5 Hz), 7.61 (1H, dd, J=2.2,12.7 Hz), 7.76 (1H, s).

[0319] IR (Neat) cm⁻¹: 1698, 1653, 1609, 1523, 1438, 1427.

[0320] Mass m/z: 472 (M⁺).

Example 20

[0321] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

[0322] 4-(4-tert-Butoxycarbonyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazine-3-o ne (220 mg,0.47 mmol) was dissolved in ice-cold trifluoroacetic acid (2 mL), and atthe same temperature, the mixture was stirred for 15 minutes. Water (10mL) was added to the reaction mixture. The mixture was alkalinized withpotassium carbonate and extracted twice with chloroform (20 mL) Theextracts were washed with brine (20 mL) and dried over anhydrous sodiumsulfate. The solvent was distilled off. The residue was recrystallizedfrom chloroform-hexane to yield the title compound as pale yellow prisms(120 mg, 69.2%).

[0323] Melting point: 111.5-118.0° C.

[0324]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.59 (4H, m), 1.36-1.47 (1H, m),2.55 (4H, br), 2.96 (4H, t, J=4.9 Hz), 3.56 (2H, d, J=1.5 Hz), 3.95 (3H,s), 4.09 (2H, d, J=7.3 Hz), 7.04 (1H, dd, J=8.5, 8.5 Hz), 7.53 (1H, ddd,J=1.2, 2.2, 8.5 Hz), 7.62 (1H, dd, J=2.2, 12.7 Hz), 7.76 (1H, t, J=1.5Hz).

[0325] IR (KBr) cm⁻¹: 3328, 1648, 1605, 1520, 1437.

[0326] Mass m/z: 372 (M⁺).

Example 21

[0327] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[0328] Following the procedure of Example 4,2-cyclopropyl-methyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)-methyl-2H-pyridazin-3-one was reacted to yield the titlecompound as slightly yellow prisms (yield: 94.5%).

[0329] Melting point: 139.1-142.4° C.

[0330]¹H NMR (400 MHz, DMSO-d₆) δ: 0.42-0.56 (4H, m), 1.29-1.39 (1H, m),3.40 (4H, br), 3.70 (4H, br), 3.91 (3H, s), 4.16 (2H, d, J=7.3 Hz), 4.16(2H, brs), 7.31 (1H, dd, J=8.5, 8.5 Hz), 7.71-7.73 (2H, m), 8.41 (1H,brs).

[0331] IR (KBr) cm⁻¹: 3435, 1660, 1610, 1526, 1440, 1291.

Example 22

[0332] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[0333] Following the procedure of Example 1 (10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a palebrown oil (yield: 83.0%).

[0334]¹H NMR (400 MHz, CDCl₃) δ: 0.43-0.58 (4H, m), 1.35-1.46 (1H, m),2.71 (4H, t, J=4.9 Hz), 3.67 (4H, t, J=4.9 Hz), 3.71 (2H, s), 3.85 (2H,br), 3.94 (3H, s), 4.10 (2H, d, J=7.3 Hz), 7.01 (1H, dd, J=8.5, 8.5 Hz),7.51-7.56 (1H, m), 7.61 (1H, dd, J=2.2, 12.4 Hz), 7.73 (1H, t, J=1.5Hz).

[0335] IR (Neat) cm⁻¹: 3616, 3476, 3275, 1648, 1601, 1529.

[0336] Mass m/z: 391 (M⁺).

Example 23

[0337] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one hydrochloride

[0338] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the titlecompound as pale yellow prisms (yield: 75.9%).

[0339] Melting point: 175.2-176.8° C.

[0340]¹H NMR (400 MHz, DMSO-d₆) δ: 0.42-0.55 (4H, m), 1.28-1.39 (1H, m),3.36 (4H, br), 3.82 (4H, br), 3.92 (3H, s), 4.06 (2H, d, J=7.3 Hz), 4.49(2H, brs) 7.33 (1H, dd, J=8.5, 8.5 Hz), 7.71-7.79 (2H, m), 8.47 (1H,brs).

[0341] IR (KBr) cm⁻¹: 3162, 1652, 1604, 1531.

Example 24

[0342] Preparation of4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[0343] 1) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one

[0344] To a solution of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one (220 mg, 0.57 mmol) inN,N-dimethylformamide (5 mL) was added potassium phthalimide (160 mg,0.87 mmol), and the mixture was stirred at 80° C. for 2 hours. Water (30mL) was added to the reaction mixture. After stirring under cooling overice water, precipitated crystals were collected by filtration, dried inair, and recrystallized from chloroform-hexane to yield the titlecompound as colorless needles (202 mg, 81.0%).

[0345] Melting point: 241.7-243.6° C.

[0346]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.59 (4H, m), 1.37-1.47 (1H, m),3.90 (3H, s), 4.10 (2H, d, J=7.1 Hz), 4.91 (2H, d, J=1.2 Hz), 6.95 (1H,dd, J=8.5, 8.5 Hz), 7.29 (1H, t, J=1.2 Hz), 7.38 (1H, ddd, J=1.2, 2.2,8.5 Hz), 7.48 (1H, dd, J=2.2, 12.4 Hz), 7.76-7.81 (2H, m), 7.90-7.95(2H, m).

[0347] IR (KBr) cm⁻¹: 1712, 1653, 1614, 1524.

[0348] Mass m/z: 433 (M⁺).

[0349] 2) Preparation of4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[0350] To a solution of2-cyclopropylmethyl-6-(3-fluoro-4-methoxypheyl)-4-phthalimidomethyl-2H-pyridazin-3-one (190 mg, 0.43 mmol) in methanol (5 mL) wasadded hydrazine monohydrate (110 mg, 2.20 mmol), and the mixture washeated under reflux for 2 hours. Methanol was distilled off, andchloroform (20 mL) was added to the residue. The mixture wassuccessively washed with water (10 mL) and brine (10 mL) in this order,and was then dried over anhydrous sodium sulfate. The solvent wasdistilled off under reduced pressure. The residue was purified bypreparative thin-layer chromatography on silica gel [developing solvent:chloroform/10% w/v solution of methanol in ammonia (20/1)] to yield thetitle compound as yellow crystals (130 mg, 97.8%)

[0351]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.59 (4H, m), 1.37-1.47 (1H, m),1.51 (2H, br), 3.89 (2H, d, J=1.2 Hz), 3.95 (3H, s), 4.11 (2H, d, J=7.1Hz), 7.02 (1H, dd, J=8.5, 8.5 Hz), 7.53 (1H, ddd, J=1.2, 2.4, 8.5 Hz),7.63 (1H, dd, J=2.2, 12.7 Hz), 7.68 (1H, s).

[0352] IR (KBr) cm⁻¹: 3393, 1651, 1606, 1523, 1438, 1293.

[0353] Mass m/z: 303 (M⁺).

Example 25

[0354] Preparation of4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one hydrochloride

[0355] Following the procedure of Example 4,4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as paleyellow needles (81.0%).

[0356] Melting point: 188.2-194.2° C. (dec.)

[0357]¹H NMR (400 MHz, DMSO-d₆) δ: 0.42-0.55 (4H, m), 1.29-1.39 (1H, m),3.92 (3H, s), 4.01 (2H, s), 4.06 (2H, d, J=7.1 Hz), 7.34 (1H, dd, J=8.5,8.5 Hz) 7.71-7.78 (2H, m), 8.31 (1H, s).

[0358] IR (KBr) cm⁻¹: 3507, 3440, 1644, 1581, 1522, 1438.

Example 26

[0359] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

[0360] Following the procedure of Example 1 (10), 6(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methane-sulfonyloxy-methyl-2H-pyridazin-3-one and tert-butyl 1-piperazine-carboxylatewere reacted to yield the title compound as a yellow oil (yield: 94.3%).

[0361]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.46 (9H, s),2.27-2.40 (1H, m), 2.52 (4H, t, J=5.2 Hz), 3.50 (4H, t, J=5.2 Hz), 3.57(2H, s), 3.95 (3H, s), 4.06 (2H, d, J=7.4 Hz), 7.03 (1H, dd, J=8.6, 8.6Hz), 7.51 (1H, dd, J=1.2, 8.4 Hz), 7.60 (1H, dd, J=2.2, 12.5 Hz), 7.75(1H, s).

Example 27

[0362] Preparation of6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[0363] Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methoxy-phenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 58.5%).

[0364] Melting point: 163.0-177.0° C. (dec.)

[0365]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.8 Hz), 2.22-2.33(1H, m), 3.17 (4H, br), 3.33 (4H, t, J=5.3 Hz), 3.92 (3H, s), 3.96 (2H,s), 4.01 (2H, d, J=7.1 Hz), 7.27 (1H, dd, J=8.9, 8.9 Hz), 7.67-7.72 (2H,m), 8.22 (1H, s).

[0366] IR (KBr) cm⁻¹: 1656, 1608, 1522, 1440, 1291, 1113.

[0367] Mass m/z: 374 (M⁺)

Example 28

[0368] Preparation of6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[0369] Following the procedure of Example 1 (10),6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yieldthe title compound as a yellow oil (yield: 80.9%).

[0370]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.28-2.40 (1H,m), 2.34 (3H, s), 2.55 (4H, br), 2.63 (4H, br), 3.58 (2H, d, J=1.4 Hz),3.95 (3H, s), 4.06 (2H, d, J=7.4 Hz), 7.04 (1H, dd, J=8.6, 8.6 Hz), 7.53(1H, dd, J=1.2, 8.6 Hz), 7.61 (1H, dd, J=2.2, 12.5 Hz), 7.73 (1H, s).

Example 29

[0371] Preparation of6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[0372] Following the procedure of Example 4,6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield the title compoundas a colorless crystalline powder (yield: 73.3%).

[0373] Melting point: 236.9-237.0° C.

[0374]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.8 Hz), 2.21-2.32(1H, m), 2.77 (3H, s), 3.14 (4H, br), 3.36 (4H, br), 3.87 (2H, s), 3.91(3H, s), 4.00 (2H, d, J=7.1 Hz), 7.26 (1H, dd, J=8.5, 8.5 Hz), 7.66-7.71(2H, m), 8.12 (1H, s).

[0375] IR (KBr) cm⁻¹: 1655, 1606, 1524, 1440, 1291, 1113, 1022.

[0376] Mass m/z: 388 (M⁺)

Example 30

[0377] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

[0378] Following the procedure of Example 1 (10),6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-one and diethanolamine were reacted to yield thetitle compound as a yellow oil (yield: 87.2%).

[0379]¹H NMR (400 MHz, CDCl₃) δ: 0.96 (6H, d, J=6.8 Hz), 2.27-2.39 (1H,m), 2.71 (4H, t, J=5.0 Hz), 3.67 (4H, t, J=5.0 Hz), 3.70 (2H, s), 3.93(3H, s), 4.07 (2H, d, J=7.4 Hz), 7.01 (1H, dd, J=8.6, 8.6 Hz), 7.53 (1H,dd, J=1.4, 8.4 Hz), 7.61 (1H, dd, J=2.2, 12.5 Hz), 7.72 (1H, s).

Example 31

[0380] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one hydrochloride

[0381] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the titlecompound as colorless flakes (yield: 89.0%).

[0382] Melting point: 129.8-133.1° C.

[0383]¹H NMR (400 MHz, DMSO-d₆) δ: 0.95 (6H, d, J=6.8 Hz), 2.23-2.34(1H, m), 3.34 (4H, t, J=5.1 Hz), 3.83 (4H, t, J=5.2 Hz), 3.92 (3H, s),4.03 (2H, d, J=7.0 Hz), 4.44 (2H, s), 7.29 (1H, dd, J=8.7, 8.7 Hz),7.69-7.75 (2H, m), 8.46 (1H, s).

[0384] IR (KBr) cm⁻¹: 1652, 1601, 1525, 1440, 1277.

[0385] Mass m/z: 362 (M⁺-CH₂OH)

Example 32

[0386] Preparation of4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

[0387] Following the procedure of Example 7,6-3-(fluoro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield thetitle compound as a yellow oil (yield: 88.6%).

[0388]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.30-2.40 (1H,m), 2.36 (6H, s), 3.50 (2H, s), 3.93 (3H, s), 4.07 (2H, d, J=7.2 Hz),7.02 (1H, dd, J=8.6, 8.6 Hz), 7.55 (1H, d, J=8.6 Hz), 7.63 (1H, dd,J=2.1, 12.5 Hz), 7.75 (1H, s).

Example 33

[0389] Preparation of4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

[0390] Following the procedure of Example 4,4-dimethyl-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the title compound ascolorless needles (yield: 81.0%).

[0391] Melting point: 212.4-212.8° C.

[0392]¹H NMR (400 MHz, DMSO-d₆) δ: 0.95 (6H, d, J=6.8 Hz), 2.23-2.33(1H, m), 2.81 (6H, s), 3.92 (3H, s), 4.04 (2H, s, J=7.1 Hz), 4.27 (2H,s), 7.29 (1H, dd, J=8.1, 8.1 Hz), 7.70-7.75 (2H, m), 8.51 (1H, s).

[0393] IR (KBr) cm⁻¹: 1652, 1607, 1522, 1439, 1292, 1112.

[0394] Mass m/z: 333 (M⁺)

Example 34

[0395] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

[0396] 1) Preparation of 4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one

[0397] Following the procedure of Example 1 (5),4-carboxy-6-phenyl-2H-pyridazin-3-one was reacted to yield the titlecompound as pale yellow crystals (yield: 98.9%).

[0398] Melting point: 202.5-206.2° C.

[0399]¹H NMR (400 MHz, CDCl₃) δ: 4.01 (3H, s), 7.45-7.54 (3H, m),7.78-7.85 (2H, m), 8.38 (1H, s), 11.86 (1H, br).

[0400] IR (KBr) cm⁻¹: 1717, 1670, 1443, 1259.

[0401] Mass m/z: 230 (M⁺)

[0402] 2) Preparation of2-isobutyl-4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-on e

[0403] Following the procedure of Example 1 (6),4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one was reacted to yield thetitle compound as a yellow oil (yield: 94.1%).

[0404]¹H NMR (400 MHz, CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 2.33-2.44 (1H,m), 3.98 (3H, s), 4.14 (2H, d, J=7.4 Hz), 7.42-7.51 (3H, m), 7.79-7.83(2H, m), 8.27 (1H, s).

[0405] 3) Preparation of4-carboxy-2-isobutyl-6-phenyl-2H-pyridazin-3-one

[0406] Following the procedure of Example 1 (7),2-isobutyl-4-methoxycarbonyl-6-phenyl-2H-pyridazin-3-one was reacted toyield the title compound as colorless fine-needles (yield: 82.5%).

[0407] Melting point: 120.5-121.0° C.

[0408]¹H NMR (400 MHz, CDCl₃) δ: 1.03 (6H, d, J=6.6 Hz), 2.34-2.45 (1H,m), 4.23 (2H, d, J=7.4 Hz), 7.49-7.54 (3H, m), 7.84-7.89 (2H, m), 8.69(1H, s), 14.20 (1H, s).

[0409] IR (KBr) cm⁻¹: 3448, 2956, 1741, 1636, 1418, 1116.

[0410] Mass m/z: 272 (M⁺)

[0411] 4) Preparation of4-hydroxymethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

[0412] Following the procedure of Example 1 (8),4-carboxy-2-isobutyl-6-phenyl-2H-pyridazin-3-one was reacted to yieldthe title compound as colorless fine-needles (yield: 22.3%).

[0413]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.29-2.40 (1H,m), 3.67 (1H, br), 4.08 (2H, d, J=7.4 Hz), 4.72 (2H, d, J=3.9 Hz),7.39-7.49 (3H, m), 7.76 (1H, t, J=1.4 Hz), 7.79-7.84 (2H, m).

[0414] 5) Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyrid azin-3-one

[0415] Following the procedure of Example 1 (9),4-hydroxymethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one was reacted toyield the title compound as colorless fine-needles (yield: 68.4%).

[0416] Melting point: 129.7° C.

[0417]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.30-2.41 (1H,m), 3.17 (3H, s), 4.10 (2H, d, J=7.2 Hz), 5.28 (2H, d, J=1.2 Hz),7.43-7.52 (3H, m), 7.79-7.82 (3H, m).

[0418] IR (KBr) cm⁻¹: 3442, 2963, 1658, 1611, 1355, 1165, 872.

[0419] Mass m/z: 336 (M⁺)

[0420] 6) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

[0421] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxy-6-phenyl-2H-pyridazin-3-one andtert-butyl 1-piperazinecarboxylate were reacted in N,N-dimethylformamideas a solvent to yield the title compound as a yellow oil (yield: 83.5%).

[0422]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 1.47 (9H, s),2.53 (4H, t, J=4.9 Hz), 3.50 (4H, t, J=4.9 Hz), 3.59 (2H, d, J=11.0 Hz),4.09 (2H, d, J=7.2 Hz), 7.40-7.50 (3H, m), 7.80-7.84 (3H, m).

Example 35

[0423] Preparation of2-isobutyl-6-phenyl-4-(1-piperazinyl)-methyl-2H-pyrid azin-3-onedihydrochloride

[0424] Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-phenyl-2H-pyridazin-3-onewas reacted to yield the title compound as a white solid (yield: 67.9%).

[0425] Melting point: 154.3-159.5° C.

[0426]¹H NMR (400 MHz, CDCl₃) δ: 0.94 (6H, d, J=6.8 Hz), 2.20-2.32 (1H,m), 2.86 (4H, br), 3.21 (4H, br), 3.71 (2H, s), 4.01 (2H, d, J=7.2 Hz),7.42-7.53 (3H, m), 7.84-7.89 (2H, m), 7.96 (1H, s).

[0427] IR (KBr) cm⁻¹: 1656, 1610, 1445, 694.

[0428] Mass m/z: 326 (M⁺)

Example 36

[0429] Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-phenyl-2H-pyridazin-3-one

[0430] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one and1-methylpiperazine were reacted to yield the title compound as a yellowoil (yield: 77.1%).

[0431]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.30-2.40 (1H,m), 2.34 (3H, s), 2.55 (4H, br), 2.64 (4H, br), 3.59 (2H, d, J=1.4 Hz),4.08 (2H, d, J=7.2 Hz), 7.40-7.50 (3H, m), 7.78-7.84 (3H, m)

Example 37

[0432] Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-phenyl-2H-pyridazin-3-onedihydrochloride

[0433] Following the procedure of Example 4,2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-phenyl-2H-pyr idazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 66.3%).

[0434] Melting point: 243.8-244.3° C.

[0435]¹H NMR (400 MHz, DMSO-d₆) δ: 0.95 (6H, d, J=6.8 Hz), 2.22-2.34(1H, m), 2.76 (3H, s), 3.01 (4H, br), 3.30 (4H, br), 3.77 (2H, s), 4.02(2H, d, J=7.2 Hz), 7.43-7.53 (3H, m), 7.85-7.89 (2H, m), 8.02 (1H, s).

[0436] IR (KBr) cm⁻¹: 2960, 1653, 1610, 1446.

[0437] Mass m/z: 340 (M⁺)

Example 38

[0438] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one

[0439] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one anddiethanolamine were reacted to yield the title compound as a yellow oil(yield: 38.7%).

[0440]¹H NMR (400 MHz, CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 2.29-2.40 (1H,m), 2.79 (4H, br), 3.70 (4H, br), 3.80 (2H, s), 4.09 (2H, d, J=7.4 Hz),7.39-7.48 (3H, m), 7.81-7.87 (3H, m)

Example 39

[0441] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-one hydrochloride

[0442] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless flakes (yield:68.4%).

[0443] Melting point: 131.6-132.0° C.

[0444]¹H NMR (400 MHz, DMSO-d₆) δ: 0.96 (6H, d, J=6.6 Hz), 2.25-2.35(1H, m), 3.35 (4H, t, J=5.1 Hz), 3.84 (4H, t, J=5.4 Hz), 4.06 (2H, d,J=7.1 Hz), 4.47 (2H, s), 7.45-7.54 (3H, m), 7.90-7.94 (2H, m), 8.48 (1H,s).

[0445] IR (KBr) cm⁻¹: 1655, 1610, 1421, 1053.

[0446] Mass m/z: 314 (M⁺-CH₂OH)

Example 40

[0447] Preparation of4-dimethylaminomethyl-2-isobutyl-6-phenyl-2H-pyridazi n-3-one

[0448] Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-phenyl-2H-pyridazin-3-one anddimethylamine were reacted to yield the title compound as a yellow oil(yield: 81.1%).

[0449]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.32-2.41 (1H,m), 2.35 (6H, s), 3.51 (2H, d, J=1.2 Hz), 4.09 (2H, d, J=7.2 Hz),7.38-7.48 (3H, m), 7.80-7.87 (3H, m)

Example 41

[0450] Preparation of4-dimethylaminomethyl-2-isobutyl-6-phenyl-2H-pyridazi n-3-onehydrochloride

[0451] Following the procedure of Example 4,4-dimethyl-aminomethyl-2-isobutyl-6-phenyl-2H-pyridazin-3-o ne wasreacted to yield the title compound as pale yellow flakes (yield:71.5%).

[0452] Melting point: 221.7-222.3° C.

[0453]¹H NMR (400 MHz, DMSO-d₆) δ: 0.96 (6H, d, J=6.8 Hz), 2.24-2.35(1H, m), 2.82 (6H, s), 4.06 (2H, d, J=7.1 Hz), 4.29 (2H, s), 7.44-7.54(3H, m), 7.90-7.94 (2H, m), 8.54 (1H, s).

[0454] IR (KBr) cm⁻¹: 1648, 1610, 1460, 1052.

[0455] Mass m/z: 285 (M⁺)

Example 42

[0456] Preparation of4-(4-benzyl-1-piperazinyl)methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

[0457] 1) Preparation of2-isobutyl-4-methoxycarbonyl-6-(4-methylphenyl)-2H-pyri dazin-3-one

[0458] Following the procedure of Example 1 (6),4-methoxy-carbonyl-6-(4-methylphenyl)-2H-pyridazin-3-one was reacted toyield the title compound as slightly yellow needles (yield: 91.6%).

[0459] Melting point: 67.0-70.1° C.

[0460]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.32-2.43 (1H,m), 2.41 (3H, s), 3.98 (3H, s), 4.13 (2H, d, J=7.3 Hz), 7.28 (2H, d,J=8.3 Hz), 7.70 (2H, d, J=8.3 Hz), 8.24 (1H, s).

[0461] IR (KBr) cm⁻¹: 1718, 1663, 1605.

[0462] Mass m/z: 300 (M⁺)

[0463] 2) Preparation of4-carboxy-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

[0464] Following the procedure of Example 1 (7),2-isobutyl-4-methoxycarbonyl-6-(4-methylphenyl)-2H-pyridazi n-3-one wasreacted to yield the title compound as slightly yellow needles (yield:86.7%).

[0465] Melting point: 162.1-165.4° C.

[0466]¹H NMR (400 MHz, CDCl₃) δ: 1.02 (6H, d, J=6.8 Hz), 2.34-2.44 (1H,m), 2.47 (3H, s), 4.21 (2H, d, J=7.3 Hz), 7.31 (2H, d, J=8.3 Hz), 7.75(2H, d, J=8.3 Hz), 8.66 (1H, s), 14.26 (1H, s).

[0467] IR (KBr) cm⁻¹: 1740, 1633, 1571, 1425.

[0468] Mass m/z: 286 (M⁺)

[0469] 3) Preparation of4-hydroxymethyl-2-isobutyl-6-(4-methyl-phenyl)-2H-pyrid azin-3-one

[0470] Following the procedure of Example 1 (8),4-carboxy-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one was reactedto yield the title compound as slightly yellow needles (yield: 46.0%).

[0471] Melting point: 121.9-123.5° C.

[0472]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.30-2.40 (1H,m), 2.40 (3H, s), 3.22 (1H, br), 4.08 (2H, d, J=7.3 Hz), 4.71 (2H, s),7.27 (2H, d, J=8.3 Hz), 7.77 (1H, s), 7.70 (2H, d, J=8.3 Hz).

[0473] IR (KBr) cm⁻¹: 3334, 1645, 1596, 1522.

[0474] Mass m/z: 272 (M⁺).

[0475] 4) Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-one

[0476] Following the procedure of Example 1 (9),4-hydroxy-methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as slightly yellow needles (yield:87.4%).

[0477] Melting point: 132.0-135.5° C.

[0478]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.29-2.39 (1H,m), 2.41 (3H, s), 3.17 (3H, s), 4.08 (2H, d, J=7.6 Hz), 5.27 (2H, t,J=1.5 Hz), 7.27 (2H, d, J=8.3 Hz), 7.72 (2H, d, J=8.3 Hz), 7.79 (1H, t,J=1.5 Hz).

[0479] IR (KBr) cm⁻¹: 1656, 1609, 1355, 1166.

[0480] Mass m/z: 350 (M⁺).

[0481] 5) Preparation of4-(4-benzyl-1-piperazinyl)methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

[0482] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand 1-benzylpiperazine were reacted to yield the title compound as apale yellow oil (yield: 97.7%).

[0483]¹H NMR (400 MHz, CDCl₃) δ: 0.97 (6H, d, J=6.8 Hz), 2.29-2.39 (1H,m), 2.41 (3H, s), 2.55 (4H, br), 2.61 (4H, br), 3.54 (2H, s), 3.57 (2H,d, J=1.5 Hz), 4.07 (2H, d, J=7.3 Hz), 7.22-7.36 (7H, m), 7.70 (2H, d,J=8.3 Hz), 7.77 (1H, t, J=1.5 Hz).

[0484] IR (Neat) cm⁻¹: 1657, 1652, 1518, 1455.

[0485] Mass m/z: 430 (M⁺).

Example 43

[0486] Preparation of4-(4-benzyl-1-piperazinyl)methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one dihydrochloride

[0487] Following the procedure of Example 4,4-(4-benzyl-1-piperazinyl)methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound ascolorless needles (yield: 91.8%).

[0488] Melting point: 253.5-260.1° C.

[0489]¹H NMR (400 MHz, DMSO-d₆) δ: 0.92 (6H, d, J=6.6 Hz), 2.18-2.28(1H, m), 2.34 (3H, s), 3.43(10H, br), 3.99 (2H, d, J=7.3 Hz), 4.36 (2H,brs), 7.22 (2H, d, J=8.1 Hz), 7.43-7.49 (3H, m), 7.58-7.65 (2H, m), 7.78(2H, d, J=8.1 Hz), 8.30 (1H, brs).

[0490] IR (KBr) cm⁻¹: 1660, 1617, 1452.

Example 44

[0491] Preparation of4-dimethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

[0492] Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a slightlyyellow oil (yield: 96.6%).

[0493]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.38-2.41 (1H,m), 2.35 (6H, s), 2.40 (3H, s), 3.50 (2H, d, J=1.5 Hz), 4.08 (2H, d,J=7.3 Hz), 7.26 (2H, d, J=8.1 Hz), 7.73 (2H, d, J=8.1 Hz), 7.78 (1H, t,J=1.5 Hz).

[0494] IR (Neat) cm⁻¹: 1652, 1609, 1518, 1455.

[0495] Mass m/z: 299 (M⁺).

Example 45

[0496] Preparation of4-dimethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onehydrochloride

[0497] Following the procedure of Example 4,4-dimethyl-aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyr idazin-3-onewas reacted to yield the title compound as colorless needles (yield:91.8%).

[0498] Melting point: 237.6-239.6° C.

[0499]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.8 Hz), 2.19-2.30(1H, m), 2.37 (3H, s), 2.81 (6H, s), 4.02 (2H, d, J=7.0 Hz), 4.30 (2H,s), 7.34 (2H, d, J=8.1 Hz), 7.81 (2H, d, J=8.1 Hz), 8.46 (1H, s).

[0500] IR (KBr) cm⁻¹: 1648, 1605, 1460, 1421.

Example 46

[0501] Preparation of4-diethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

[0502] Following the procedure of Example 9 (4),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand diethylamine were reacted to yield the title compound as a paleyellow oil (yield: 95.0%).

[0503]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 1.07 (6H, t,J=7.1 Hz), 2.30-2.42 (1H, m), 2.40 (3H, s), 2.60 (4H, q, J=7.1 Hz), 3.60(2H, d, J=1.5 Hz), 4.08 (2H, d, J=7.3 Hz), 7.26 (2H, d, J=8.1 Hz), 7.73(2H, d, J=8.1 Hz), 7.89 (1H, t, J=1.5 Hz).

[0504] IR (Neat) cm⁻¹: 1652, 1609, 1518, 1465, 1455.

[0505] Mass m/z: 327 (M⁺)

Example 47

[0506] Preparation of4-diethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onehydrochloride

[0507] Following the procedure of Example 4,4-diethyl-aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyri dazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 93.8%).

[0508] Melting point: 203.9-207.0° C.

[0509]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 1.27 (6H, t,J=7.2 Hz), 2.20-2.30 (1H, m), 2.37 (3H, s), 3.09-3.24 (4H, m), 4.03 (2H,d, J=7.1 Hz), 4.28 (2H, d, J=5.4 Hz), 7.34 (2H, d, J=8.1 Hz), 7.82 (2H,d, J=8.1 Hz), 8.55 (1H, s).

[0510] IR (KBr) cm⁻¹: 1652, 1610, 1523, 1481, 1468.

Example 48

[0511] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

[0512] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a paleyellow oil (yield: 95.0%).

[0513]¹H NMR (400 MHz, CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 2.28-2.41 (1H,m), 2.40 (3H, s), 2.71 (4H, t, J=5.0 Hz), 3.66 (4H, t, J=5.0 Hz), 3.70(2H, s), 3.78 (2H, br), 4.09 (2H, d, J=7.6 Hz), 7.26 (2H, d, J=8.1 Hz)7.68 (1H, s), 7.70 (2H, d, J=8.1 Hz).

[0514] IR (Neat) cm⁻¹: 3392, 1645, 1600, 1520.

[0515] Mass m/z: 341 (M⁺-H₂O).

Example 49

[0516] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one hydrochloride

[0517] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the title compound asslightly yellow needles (yield: 86.4%).

[0518] Melting point: 158.9-161.5° C.

[0519]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.19-2.30(1H, m), 2.37 (3H, s), 3.27-3.46 (4H, m), 3.77-3.85 (4H, m), 4.02 (2H,d, J=7.3 Hz), 4.50 (2H, brs), 5.35 (2H, br), 7.34 (2H, d, J=8.1 Hz),7.81 (2H, d, J=8.1 Hz), 8.46 (1H, s).

[0520] IR (KBr) cm⁻¹: 3292, 1664, 1615, 1423.

Example 50

[0521] Preparation of4-aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyrida zin-3-one

[0522] 1) Preparation of2-isobutyl-6-(4-methylphenyl)-4-phthalimidomethyl-2H-py ridazin-3-one

[0523] Following the procedure of Example 24 (1),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:98.2%).

[0524] Melting point: 221.6-223.8° C.

[0525]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.27-2.41 (1H,m), 2.36 (3H, s), 4.08 (2H, d, J=7.3 Hz), 4.91 (2H, d, J=1.5 Hz), 7.20(2H, d, J=8.1 Hz), 7.32 (1H, t, J=1.5 Hz), 7.56 (2H, d, J=8.1 Hz),7.75-7.80 (2H, m), 7.89-7.94 (2H, m).

[0526] IR (KBr) cm⁻¹: 1767, 1721, 1655, 1616.

[0527] Mass m/z: 401 (M⁺).

[0528] 2) Preparation of4-aminomethyl-2-isobutyl-6-(4-methyl-phenyl)-2H-pyridaz in-3-one

[0529] Following the procedure of Example 24 (2),2-isobutyl-6-(4-methylphenyl)-4-phthalimidomethyl-2H-pyrida zin-3-onewas reacted to yield the title compound as colorless prisms (yield:98.1%).

[0530] Melting point: 74.9-77.9° C.

[0531]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.9 Hz), 1.68 (2H, br),2.28-2.42 (1H, m), 2.40 (3H, s), 3.87 (2H, d, J=1.2 Hz), 4.07 (2H, d,J=7.3 Hz), 7.26 (2H, d, J=8.0 Hz), 7.69 (1H, t, J=1.5 Hz), 7.71 (2H, d,J=8.0 Hz).

[0532] IR (KBr) cm⁻¹: 3363, 3289, 1648, 1604, 1519.

[0533] Mass m/z: 271 (M⁺).

Example 51

[0534] Preparation of4-aminomethyl-2-isobutyl-6-(4-methyl-phenyl)-2H-pyrid azin-3-onehydrochloride

[0535] Following the procedure of Example 4,4-aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as pale yellow prisms (yield:93.1%).

[0536] Melting point: 207.4-209.4° C. (dec.)

[0537]¹H NMR (400 MHz, DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.19-2.30(1H, m), 2.37 (3H, s), 4.01 (2H, d, J=7.1 Hz), 4.02 (2H, s), 7.34 (2H,d, J=8.1 Hz) 7.80 (2H, d, J=8.1 Hz), 8.26 (1H, s).

[0538] IR (KBr) cm⁻¹: 1655, 1616, 1520, 1467.

Example 52

[0539] Preparation of4-(1,3-dihydroxypropan-2-yl)amino-methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

[0540] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand 2-amino-1,3-propanediol were reacted to yield the title compound ascolorless needles (yield: 83.7%)

[0541] Melting point: 134.1-135.2° C.

[0542]¹H NMR (400 MHz, CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 2.29-2.39 (1H,m), 2.40 (3H, s), 2.60 (3H, br), 2.82-2.87 (1H, m), 3.64 (2H, dd, J=5.6,11.2 Hz), 3.80 (2H, dd, J=4.5, 11.2 Hz), 3.86 (2H, d, J=1.0 Hz), 4.07(2H, d, J=7.3 Hz), 7.26 (2H, d, J=8.1 Hz), 7.71 (2H, d, J=8.1 Hz), 7.74(1H, s).

[0543] IR (KBr) cm⁻¹: 3408, 3293, 1641, 1592, 1520.

[0544] Mass m/z: 345 (M⁺).

Example 53

[0545] Preparation of4-(1,3-dihydroxypropan-2-yl)amino-methyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-onehydrochloride

[0546] Following the procedure of Example 4,4-N-(1,3-dihydroxypropan-2-yl)aminomethyl-2-isobutyl-6-(4-methyl-phenyl)-2H-pyridazin-3-one was reacted to yield the title compoundas colorless needles (yield: 95.7%).

[0547] Melting point: 191.2-193.0° C.

[0548]¹H NMR (400 MHz, DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.19-2.30(1H, m), 2.37 (3H, s), 3.29 (1H, br), 3.60-3.78 (4H, m), 4.02 (2H, d,J=7.1 Hz), 4.29 (2H, s), 5.40 (2H, brs), 7.34 (2H, d, J=8.1 Hz), 7.81(2H, d, J=8.1 Hz), 8.38 (1H, s).

[0549] IR (KBr) cm⁻¹: 3392, 1652, 1610.

Example 54

[0550] Preparation of2-isobutyl-4-methylaminomethyl-6-(4-methylphenyl)-2H-pyridazin-3-one

[0551] Following the procedure of Example 9 (4),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand methylamine were reacted to yield the title compound as a slightlyyellow oil (yield: 94.5%).

[0552]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.87 (1H, br),2.29-2.42 (1H, m), 2.40 (3H, s), 2.50 (3H, s), 3.76 (2H, d, J=1.2 Hz),4.07 (2H, d, J=7.3 Hz), 7.26 (2H, d, J=8.1 Hz), 7.67 (1H, t, J=1.2 Hz),7.71 (2H, d, J=8.1 Hz).

[0553] IR (Neat) cm⁻¹: 3317, 1652, 1607.

[0554] Mass m/z: 285 (M⁺).

Example 55

[0555] Preparation of2-isobutyl-4-methylaminomethyl-6-(4-methylphenyl)-2H-pyridazin-3-onehydrochloride

[0556] Following the procedure of Example 4,2-isobutyl-4-methylaminomethyl-6-(4-methylphenyl)-2H-pyrida zin-3-onewas reacted to yield the title compound as colorless needles (yield:97.5%).

[0557] Melting point: 198.3-201.0° C.

[0558]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.8 Hz), 2.20-2.31(1H, m), 2.37 (3H, s), 2.65 (3H, s), 4.02 (2H, d, J=7.3 Hz), 4.12 (2H,s), 7.34 (2H, d, J=8.1 Hz), 7.80 (2H, d, J=8.1 Hz), 8.35 (1H, s).

[0559] IR (KBr) cm⁻¹: 3085, 1652, 1612.

Example 56

[0560] Preparation of4-(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one

[0561] Following the procedure of Example 9 (4),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-methylphenyl)-2H-pyridazin-3-oneand 2-aminoethanol were reacted to yield the title compound as aslightly yellow oil (yield: 80.3%).

[0562]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.20-2.38 (3H,m), 2.39 (3H, s), 2.84 (2H, t, J=5.1 Hz), 3.72 (2H, t, J=5.1 Hz), 3.82(2H, d, J=1.2 Hz), 4.07 (2H, d, J=7.3 Hz), 7.26 (2H, d, J=8.1 Hz), 7.68(1H, s), 7.70 (2H, d, J=8.1 Hz).

[0563] IR (Neat) cm⁻¹: 3429, 1652, 1601, 1519.

[0564] Mass m/z: 315 (M⁺).

Example 57

[0565] Preparation of4-(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one hydrochloride

[0566] Following the procedure of Example 4,4-N-(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound ascolorless needles (yield: 93.4%).

[0567] Melting point: 190.8-191.9° C.

[0568]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.20-2.31(1H, m), 2.37 (3H, s), 3.12 (2H, t, J=5.4 Hz), 3.70-3.76 (2H, m), 4.02(2H, d, J=7.3 Hz), 4.18 (2H, s), 5.30 (1H, br), 7.34 (2H, d, J=8.3 Hz),7.81 (2H, d, J=8.3 Hz), 8.36 (1H, s).

[0569] IR (KBr) cm⁻¹: 3491, 1652, 1611.

Example 58

[0570] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-(4-trifluoromethyl-phenyl)-2H-pyridazin-3-one

[0571] 1) Preparation of ethyl2-ethoxycarbonyl-2-hydroxy-4-(4-trifluoromethylphenyl)-4-oxo-butanoate

[0572] Following the procedure of Example 1 (3),4′-(trifluoromethyl)acetophenone was reacted to yield the title compoundas pale yellow crystals (yield: 80.8%).

[0573]¹H NMR (400 MHz, CDCl₃) δ: 1.30 (6H, t, J=7.1 Hz), 3.85 (2H, s),4.22 (1H, s), 4.31 (4H, q, J=7.1 Hz), 7.76 (2H, d, J=8.6 Hz), 8.07 (2H,d, J=8.6 Hz).

[0574] IR (KBr) cm⁻¹: 3446, 1750, 1727, 1691.

[0575] Mass m/z: 343 (M⁺-H₂O).

[0576] 2) Preparation of4-carboxy-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-on e

[0577] Following the procedure of Example 1 (4), ethyl2-ethoxycarbonyl-2-hydroxy-4-(4-trifluoromethylphenyl)-4-ox obutanoatewas reacted to yield the title compound as a pale brown crystallinepowder (yield: 91.4%).

[0578] 3) Preparation of4-methoxycarbonyl-6-(4-trifluoromethyl-phenyl)-2H-pyrid azin-3-one

[0579] Following the procedure of Example 1 (5),4-carboxy-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one was reacted toyield the title compound as slightly yellow crystalline powder (yield:88.5%).

[0580]¹H NMR (400 MHz, CDCl₃) δ: 4.02 (3H, s), 7.75 (2H, d, J=8.2 Hz),7.95 (2H, d, J=8.2 Hz), 8.39 (1H, s), 11.69 (1H, br).

[0581] IR (KBr) cm⁻¹: 3218, 3140, 3097, 1720, 1678, 1326.

[0582] Mass m/z: 298 (M⁺).

[0583] 4) Preparation of2-isobutyl-4-methoxycarbonyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

[0584] Following the procedure of Example 1 (6),4-methoxy-carbonyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as yellow crystals (yield: 82.2%).

[0585]¹H NMR (400 MHz, CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 2.32-2.43 (1H,m), 3.99 (3H, s), 4.15 (2H, d, J=7.2 Hz), 7.74 (2H, d, J=8.4 Hz), 7.93(2H, d, J=8.4 Hz), 8.12 (1H, s).

[0586] IR (Neat) cm⁻¹: 2961, 1746, 1670, 1327, 1115, 1068.

[0587] Mass m/z: 354 (M⁺).

[0588] 5) Preparation of4-carboxy-2-isobutyl-6-(4-trifluoro-methylphenyl)-2H-py ridazin-3-one

[0589] Following the procedure of Example 1 (7),2-isobutyl-4-methoxycarbonyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless fine-needles(yield: 91.6%).

[0590] Melting point: 184.4-185.0° C.

[0591]¹H NMR (400 MHz, CDCl₃) δ: 1.03 (6H, d, J=6.6 Hz), 2.34-2.45 (1H,m), 4.25 (2H, d, J=7.2 Hz), 7.78 (2H, d, J=8.2 Hz), 7.99 (2H, d, J=8.2Hz), 8.70 (1H, s), 14.02 (1H, s).

[0592] IR (KBr) cm⁻¹: 3447, 1739, 1631, 1570, 1330, 1174, 1114, 1070,847.

[0593] Mass m/z: 340 (M⁺)

[0594] 6) Preparation of4-hydroxymethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

[0595] Following the procedure of Example 1 (8),4-carboxy-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridaz in-3-one wasreacted to yield the title compound as colorless fine-needles (yield:28.1%).

[0596] Melting point: 145.8-146.5° C.

[0597]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.30-2.41 (1H,m), 2.96 (1H, t, J=5.9 Hz), 4.11 (2H, d, J=7.4 Hz), 4.74 (2H, dd, J=1.4,5.8 Hz), 7.70-7.74 (3H, m), 7.94 (2H, d, J=8.2 Hz).

[0598] IR (KBr) cm⁻¹: 3339, 1646, 1596, 1328, 1131, 1070, 848.

[0599] 7) Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

[0600] Following the procedure of Example 1 (9),4-hydroxy-methyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless fine-needles(yield: 89.9%).

[0601] Melting Point: 122.9-123.8° C.

[0602]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.29-2.40 (1H,m), 3.18 (3H, s), 4.11 (2H, d, J=7.2 Hz), 5.29 (2H, d, J=1.4 Hz), 7.73(2H, d, J=8.2 Hz), 7.83 (1H, t, J=1.4 Hz), 7.93 (2H, d, J=8.2 Hz).

[0603] IR (KBr) cm⁻¹: 3447, 1659, 1613, 1359, 1329, 1169, 1123, 1071,846.

[0604] Mass m/z: 404 (M⁺)

[0605] 8) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

[0606] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate werereacted to yield the title compound as a yellow oil (yield: 83.5%).

[0607]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.47 (9H, s),2.29-2.41 (1H, m), 2.53 (4H, t, J=4.9 Hz), 3.51 (4H, t, J=4.8 Hz), 3.60(2H, s), 4.10 (2H, d, J=7.4 Hz), 7.72 (2H, d, J=8.2 Hz), 7.84 (1H, s),7.94 (2H, d, J=8.2 Hz)

Example 59

[0608] Preparation of2-isobutyl-4-(1-piperazinyl)methyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one dihydrochloride

[0609] Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 95.0%).

[0610] Melting point: 210.8-212.5° C.

[0611]¹H NMR (400 MHz, DMSO-d₆) δ: 0.96 (6H, d, J=6.6 Hz), 2.22-2.35(1H, m), 3.12 (4H, br), 3.30 (4H, t, J=5.2 Hz), 3.92 (2H, s), 4.05 (2H,d, J=7.1 Hz), 7.84 (2H, d, J=8.3 Hz), 8.11 (2H, d, J=8.1 Hz), 8.25 (1H,s).

[0612] IR (KBr) cm⁻¹: 1656, 1608, 1328, 1125, 1069.

[0613] Mass m/z: 394 (M⁺)

Example 60

[0614] Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

[0615] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yieldthe title compound as a yellow oil (yield: 81.1%).

[0616]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.30-2.41 (1H,m), 2.33 (3H, s), 2.53 (4H, br), 2.63 (4H, br), 3.60 (2H, s), 4.10 (2H,d, J=7.2 Hz), 7.72 (2H, d, J=8.2 Hz), 7.83 (1H, s), 7.94 (2H, d, J=8.2Hz).

Example 61

[0617] Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one dihydrochloride

[0618] Following the procedure of Example 4,2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one was reacted to yield the title compoundas colorless flakes (yield: 88.6%).

[0619] Melting point: 249.9-252.8° C.

[0620]¹H NMR (400 MHz, DMSO-d₆) δ: 0.95 (6H, d, J=6.8 Hz), 2.22-2.35(1H, m), 2.77 (3H, s), 3.14 (4H, br), 3.35 (4H, br), 3.88 (2H, s), 4.05(2H, d, J=7.2 Hz), 7.84 (2H, d, J=8.2 Hz), 8.10 (2H, d, J=8.0 Hz), 8.19(1H, s).

[0621] IR (KBr) cm⁻¹: 2966, 1653, 1610, 1328, 1125, 1069.

[0622] Mass m/z: 408 (M⁺)

Example 62

[0623] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

[0624] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one and diethanolamine were reacted to yield thetitle compound as a yellow oil (yield: 79.5%).

[0625]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.29-2.40 (1H,m), 2.72 (4H, br), 3.67 (4H, t, J=4.2 Hz), 3.72 (2H, s), 4.10 (2H, d,J=7.4 Hz), 7.70 (2H, d, J=7.6 Hz), 7.82 (1H, s), 7.94 (2H, d, J=8.2 Hz).

Example 63

[0626] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onehydrochloride

[0627] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-(4-trifluoromethyl-phenyl)-2H-pyridazin-3-one was reacted to yield the titlecompound as a colorless crystalline powder (yield: 58.2%).

[0628] Melting point: 134.9-135.4° C.

[0629]¹H NMR (400 MHz, DMSO-d₆) δ: 0.97 (6H, d, J=6.6 Hz), 2.25-2.36(1H, m), 3.34 (4H, br), 3.83 (4H, t, J=5.1 Hz), 4.07 (2H, d, J=7.0 Hz),4.46 (2H, s), 7.86 (2H, d, J=8.2 Hz), 8.13 (2H, d, J=8.2 Hz), 8.55 (1H,s).

[0630] IR (KBr) cm⁻¹: 1653, 1605, 1319, 1125, 1069.

[0631] Mass m/z: 395 (M⁺-H₂O)

Example 64

[0632] Preparation of4-dimethylaminomethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one

[0633] Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as ayellow oil (yield: 80.7%).

[0634]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.31-2.40 (1H,m), 2.36 (6H, s), 3.51 (2H, d, J=1.2 Hz), 4.10 (2H, d, J=7.4 Hz), 7.71(2H, d, J=8.4 Hz), 7.83 (1H, t, J=1.4 Hz), 7.97 (2H, d, J=8.2 Hz).

Example 65

[0635] Preparation of4-dimethylaminomethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-one hydrochloride

[0636] Following the procedure of Example 4,4-dimethylaminomethyl-2-isobutyl-6-(4-trifluoromethylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow flakes (yield:93.0%).

[0637] Melting point: 242.2-242.3° C.

[0638]¹H NMR (400 MHz, DMSO-d₆) δ: 0.97 (6H, d, J=6.6 Hz), 2.25-2.36(1H, m), 2.83 (6H, s), 4.07 (2H, d, J=7.3 Hz), 4.30 (2H, s), 7.86 (2H,d, J=8.3 Hz), 8.14 (2H, d, J=8.0 Hz), 8.61 (1H, s).

[0639] IR (KBr) cm⁻¹: 2963, 1646, 1606, 1321, 1115, 1069.

[0640] Mass m/z: 353 (M⁺)

Example 66

[0641] Preparation of6-(4-biphenylyl)-4-(4-tert-butoxy-carbonyl-1-piperazinyl)methyl-2-isobutyl-2H-pyridazin-3-one

[0642] 1) Preparation of ethyl4-(4-biphenylyl)-2-ethoxycarbonyl-2-hydroxy-4-oxobutano ate

[0643] Following the procedure of Example 1 (3), 4-acetyl-biphenyl wasreacted to yield the title compound as colorless flakes (yield: 83.3%).

[0644] Melting point: 88.0-88.3° C.

[0645]¹H NMR (400 MHz, CDCl₃) δ: 1.31 (6H, t, J=7.1 Hz), 3.87 (2H, s),4.32 (4H, q, 7.1 Hz), 7.41 (1H, tt, J=1.4, 7.2 Hz), 7.48 (2H, dd, J=7.2,7.2 Hz), 7.63 (2H, d, J=7.0 Hz), 7.70 (2H, d, J=8.6 Hz), 8.04 (2H, d,J=8.6 Hz).

[0646] IR (KBr) cm⁻¹: 3449, 1736, 1680, 1604, 1301, 1244, 1204, 763.

[0647] 2) Preparation of 6-(4-biphenylyl)-4-carboxy-2H-pyridazin-3-one

[0648] Following the procedure of Example 1 (4), ethyl4-(4-biphenylyl)-2-ethoxycarbonyl-2-hydroxy-4-oxobutanoate was reactedto yield the title compound as a yellow crystalline powder (yield:90.2%).

[0649] Melting point: 299.7-300.8° C.

[0650]¹H NMR (400 MHz, DMSO-d₆) δ: 7.40 (1H, t, J=7.4 Hz), 7.49 (2H, dd,J=7.4, 7.4 Hz), 7.74 (2H, d, J=7.2 Hz), 7.82 (2H, d, J=8.4 Hz), 8.03(2H, d, J=8.4 Hz), 8.54 (1H, s).

[0651] IR (KBr) cm⁻¹: 1753, 1652, 1590, 1446, 1201, 768.

[0652] 3) Preparation of6-(4-biphenylyl)-4-methoxycarbonyl-2H-pyridazin-3-one

[0653] Following the procedure of Example 1 (5),6-(4-biphenylyl)-4-carboxy-2H-pyridazin-3-one was reacted to yield thetitle compound as a pale yellow crystalline powder (yield: 90.4%).

[0654] Melting point: 277.0-277.9° C. (dec.)

[0655]¹H NMR (400 MHz, CDCl₃) δ: 4.01 (3H, s), 7.39-7.45 (3H, m), 7.64(2H, d, J=7.2 Hz), 7.72 (2H, d, J=8.2 Hz), 7.89 (2H, d, J=8.0 Hz), 8.42(1H, s), 10.7 (1H, s).

[0656] IR (KBr) cm⁻¹: 2954, 1727, 1671, 1594, 1265, 1098, 768.

[0657] 4) Preparation of6-(4-biphenylyl)-2-isobutyl-4-methoxy-carbonyl-2H-pyrid azin-3-one

[0658] Following the procedure of Example 1 (6),6-(4-biphenylyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted toyield the title compound as yellow crystals (yield: 62.7%).

[0659] Melting point: 186.2-195.0° C.

[0660]¹H NMR (400 MHz, CDCl₃) δ: 1.01 (6H, d, J=6.8 Hz), 2.34-2.45 (1H,m), 3.99 (3H, s), 4.16 (2H, d, J=7.4 Hz), 7.39 (1H, tt, J=1.4, 7.4 Hz),7.48 (2H, dd, J=7.2, 7.2 Hz), 7.64 (2H, d, J=7.0 Hz), 7.71 (2H, d, J=8.6Hz), 7.89 (2H, d, J=8.6 Hz), 8.31 (1H, s).

[0661] 5) Preparation of6-(4-biphenylyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-on e

[0662] Following the procedure of Example 1 (7),6-(4-biphenylyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one wasreacted to yield the title compound as a colorless crystalline powder(yield: 79.2%).

[0663] Melting point: 156.9-157.6° C.

[0664]¹H NMR (400 MHz, CDCl₃) δ: 1.04 (6H, d, J=6.6 Hz), 2.36-2.46 (1H,m), 4.24 (2H, d, J=7.4 Hz), 7.41 (1H, t, J=7.4 Hz), 7.49 (2H, dd, J=7.4,7.4 Hz), 7.65 (2H, d, J=7.0 Hz), 7.74 (2H, d, J=8.4 Hz), 7.95 (2H, d,J=8.4 Hz), 8.73 (1H, s), 14.22 (1H, s).

[0665] IR (KBr) cm⁻¹: 2963, 1749, 1631, 1565, 1470, 735.

[0666] 6) Preparation of6-(4-biphenylyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazi n-3-one

[0667] Following the procedure of Example 1 (8),6-(4-biphenylyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one was reacted toyield the title compound as a while solid (yield: 15.6%).

[0668] Melting point: 146.4-147.5° C.

[0669]¹H NMR (400 MHz, CDCl₃) δ: 1.01 (6H, d, J=6.8 Hz), 2.32-2.43 (1H,m), 3.13 (1H, t, J=6.2 Hz), 4.11 (2H, d, J=7.4 Hz), 4.74 (2H, dd, J=1.2,6.2 Hz), 7.39 (1H, t, J=7.3 Hz), 7.48 (2H, dd, J=7.4, 7.4 Hz), 7.64 (2H,d, J=7.0 Hz), 7.70 (2H, d, J=8.6 Hz), 7.74 (1H, t, J=1.2 Hz), 7.90 (2H,d, J=8.6 Hz).

[0670] IR (KBr) cm⁻¹: 3431, 2961, 1647, 1596, 1077, 769.

[0671] 7) Preparation of6-(4-biphenylyl)-2-isobutyl-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one

[0672] Following the procedure of Example 1 (9),6-(4-biphenylyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one wasreacted to yield the title compound as a colorless crystalline powder(yield: 79.3%).

[0673] Melting point: 121.3-122.0° C.

[0674]¹H NMR (400 MHz, CDCl₃) δ: 1.01 (6H, d, J=6.8 Hz), 2.33-2.42 (1H,m), 3.18 (3H, s), 4.12 (2H, d, J=7.4 Hz), 5.30 (2H, d, J=1.2 Hz), 7.39(1H, t, J=7.4 Hz), 7.48 (2H, dd, J=7.6 Hz), 7.64 (2H, d, J=7.4 Hz), 7.71(2H, d, J=8.4 Hz), 7.85-7.91 (3H, m).

[0675] IR (KBr) cm⁻¹: 2964, 1658, 1610, 1354, 1165, 874, 529.

[0676] 8) Preparation of6-(4-biphenylyl)-4-(4-tert-butoxy-carbonyl-1-piperazinyl)methyl-2-isobutyl-2H-pyridazin-3-one

[0677] Following the procedure of Example 1 (10),6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-pipeazinecarboxylate were reacted toyield the title compound as a yellow oil (yield: 87.7%).

[0678]¹H NMR (400 MHz, CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 1.47 (9H, s),2.30-2.43 (1H, m), 2.54 (4H, t, J=4.9 Hz), 3.51 (4H, t, J=4.9 Hz), 3.60(2H, d, J=1.4 Hz), 4.10 (2H, d, J=7.4 Hz), 7.38 (1H, tt, J=1.4, 7.2 Hz),7.47 (2H, dd, J=7.4, 7.4 Hz), 7.64 (2H, d, J=7.0 Hz), 7.70 (2H, d, J=8.6Hz), 7.85-7.92 (3H, m).

Example 67

[0679] Preparation of6-(4-biphenylyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[0680] Following the procedure of Example 2,6-(4-biphenylyl)-4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-2H-pyridazin-3-one was reacted to yield the titlecompound as a colorless crystalline powder (yield: 51.5%).

[0681] Melting point: 226.8-228.0° C.

[0682]¹H NMR (400 MHz, DMSO-d₆) δ: 0.97 (6H, d, J=6.8 Hz), 2.25-2.36(1H, m), 3.19 (4H, br), 3.34 (4H, t, J=5.1 Hz), 3.98 (2H, s), 4.05 (2H,d, J=7.1 Hz) 7.39 (1H, t, J=7.3 Hz), 7.49 (2H, dd, J=7.7, 7.7 Hz), 7.71(2H, d, J=7.8 Hz), 7.79 (2H, d, J=8.3 Hz), 7.99 (2H, d, J=8.3 Hz), 8.29(1H, s).

[0683] IR (KBr) cm⁻¹: 1653, 1604, 1446, 771.

[0684] Mass m/z: 402 (M⁺)

Example 68

[0685] Preparation of6-(4-biphenylyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[0686] Following the procedure of Example 1 (10),6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the titlecompound as a yellow oil (yield: 68.2%).

[0687]¹H NMR (400 MHz, CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 2.30-2.43 (1H,m), 2.34 (3H, s), 2.55 (4H, br), 2.65 (4H, br), 3.61 (2H, d, J=1.2 Hz),4.10 (2H, d, J=7.2 Hz), 7.38 (1H, t, J=7.3 Hz), 7.47 (2H, dd, J=7.5, 7.5Hz), 7.64 (2H, d, J=7.2 Hz), 7.70 (2H, d, J=8.4 Hz), 7.84 (1H, s), 7.90(2H, d, J=8.4 Hz)

Example 69

[0688] Preparation of6-(4-biphenylyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[0689] Following the procedure of Example 4,6-(4-biphenylyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield the title compound as acolorless crystalline powder (yield: 69.9%).

[0690] Melting point: 262.2-263.6° C.

[0691]¹H NMR (400 MHz, DMSO-d₆) δ: 0.97 (6H, d, J=6.6 Hz), 2.26-2.35(1H, m), 2.77 (3H, s), 3.10 (4H, br), 3.34 (4H, br), 3.85 (2H, s), 4.04(2H, d, J=7.1 Hz), 7.39 (1H, t, J=7.6 Hz), 7.49 (2H, dd, J=8.0, 8.0 Hz),7.71 (2H, d, J=8.0 Hz), 7.78 (2H, d, J=8.3 Hz), 7.89 (2H, d, J=8.3 Hz),8.13 (1H, s).

[0692] IR (KBr) cm⁻¹: 1652, 1607, 1465, 1050.

[0693] Mass m/z: 416 (M⁺)

Example 70

[0694] Preparation of6-(4-biphenylyl)-4-N,N-bis(2-hydroxy-ethyl)aminomethyl-2-isobutyl-2H-pyridazin-3-one

[0695] Following the procedure of Example 1 (10),6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethanolamine were reacted to yield the titlecompound as a yellow oil (yield: 62.4%).

[0696]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.30-2.43 (1H,m), 2.73 (4H, t, J=4.8 Hz), 3.67 (4H, t, J=4.8 Hz), 3.73 (2H, s), 4.12(2H, d, J=7.4 Hz), 7.38 (1H, t, J=7.2 Hz), 7.47 (2H, dd, J=7.2, 7.2 Hz),7.63 (2H, d, J=7.4 Hz), 7.68 (2H, d, J=8.2 Hz), 7.79 (1H, s), 7.89 (2H,d, J=8.2 Hz).

Example 71

[0697] Preparation of6-(4-biphenylyl)-4-N,N-bis(2-hydroxy-ethyl)aminomethyl-2-isobutyl-2H-pyridazin-3-one hydrochloride

[0698] Following the procedure of Example 4,6-(4-biphenylyl)-4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-2H-pyridazin-3-one was reacted to yield the title compound as acolorless crystalline powder (yield: 63.9%).

[0699] Melting point: 218.3-218.6° C.

[0700]¹H NMR (400 MHz, DMSO-d₆) δ: 0.98 (6H, d, J=6.8 Hz), 2.26-2.37(1H, m), 3.36 (4H, t, J=5.1 Hz), 3.85 (4H, t, J=5.1 Hz), 4.08 (2H, d,J=7.3 Hz), 4.48 (2H, s), 7.40 (1H, tt, J=1.2, 7.3 Hz), 7.49 (2H, dd,J=7.3 Hz), 7.72 (2H, dd, J=1.2, 7.3 Hz), 7.81 (2H, d, J=8.3 Hz), 8.01(2H, d, J=8.3 Hz), 8.52 (1H, s).

[0701] IR (KBr) cm⁻¹: 1654, 1607, 1053, 847, 769.

[0702] m/z (EI): 403 (M⁺-H₂O)

Example 72

[0703] Preparation of6-(4-biphenylyl)-4-dimethylamino-methyl-2-isobutyl-2H-pyridazin-3-one

[0704] Following the procedure of Example 7,6-(4-biphenylyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as a yellow oil(yield: 87.7%).

[0705]¹H NMR (400 MHz, CDCl₃) δ: 1.00 (6H, d, J=6.6 Hz), 2.36 (6H, s),2.29-2.43 (1H, m), 3.52 (2H, d, J=1.0 Hz), 4.10 (2H, d, J=7.2 Hz), 7.37(1H, t, J=7.4 Hz), 7.46 (2H, dd, J=7.4, 7.4 Hz), 7.63 (2H, d, J=7.2 Hz),7.68 (2H, d, J=8.4 Hz), 7.85 (1H, s), 7.92 (2H, d, J=8.4 Hz).

Example 73

[0706] Preparation of6-(4-biphenylyl)-4-dimethylamino-methyl-2-isobutyl-2H-pyridazin-3-onehydrochloride

[0707] Following the procedure of Example 4,6-(4-biphenylyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyrida zin-3-onewas reacted to yield the title compound as colorless flakes (yield:58.2%).

[0708] Melting point: 243.9-244.1° C.

[0709]¹H NMR (400 MHz, DMSO-d₆) δ: 0.98 (6H, d, J=6.6 Hz), 2.26-2.37(1H, m), 2.83 (6H, s), 4.03 (2H, d, J=7.1 Hz), 4.30 (2H, S), 7.39 (1H,tt, J=1.2, 7.3 Hz), 7.49 (2H, dd, J=7.3, 7.3 Hz), 7.72 (2H, dd, J=1.2,7.1 Hz), 7.81 (2H, d, J=8.8 Hz), 8.02 (2H, d, J=8.6 Hz), 8.57 (1H, s).

[0710] IR (KBr) cm⁻¹: 1647, 1604, 1460, 1409, 1052.

[0711] Mass m/z: 361 (M⁺)

Example 74

[0712] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

[0713] Following the procedure of Example 1 (10),6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-one and tert-butyl 1-piperazine-carboxylate werereacted to yield the title compound as a yellow oil (yield: 89.0%).

[0714]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 1.47 (9H, s),2.27-2.40 (1H, m), 2.52 (4H, t, J=4.9 Hz), 3.50 (4H, t, J=5.0 Hz), 3.57(2H, d, J=1.4 Hz), 3.96 (3H, s), 4.07 (2H, d, J=7.2 Hz), 7.00 (1H, d,J=8.6 Hz), 7.66 (1H, dd, J=2.4, 8.6 Hz), 7.74 (1H, t, J=1.3 Hz), 7.86(1H, d, J=2.4 Hz).

Example 75

[0715] Preparation of6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[0716] Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-chloro-4-methoxy-phenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a white solid (yield: 70.2%).

[0717] Melting point: 203.6-204.5° C.

[0718]¹H NMR (400 MHz, DMSO-d₆) δ: 0.95 (6H, d, J=6.6 Hz), 2.20-2.34(1H, m), 3.14 (4H, br), 3.31 (4H, t, J=5.2 Hz), 3.93 (5H, s), 4.01 (2H,d, J=7.0 Hz), 7.26 (1H, d, J=8.8 Hz), 7.84 (1H, dd, J=2.4, 8.6 Hz), 7.91(1H, d, J=2.4 Hz), 8.19 (1H, s).

[0719] IR (KBr) cm⁻¹: 1654, 1608, 1507, 1289, 1065.

[0720] Mass m/z: 390 (M⁺), 392 (M⁺).

Example 76

[0721] Preparation of6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[0722] Following the procedure of Example 1 (10),6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yieldthe title compound as a yellow oil (yield: 76.1%).

[0723]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.28-2.40 (1H,m), 2.33 (3H, s), 2.53 (4H, br), 2.63 (4H, br), 3.58 (2H, d, J=1.2 Hz),3.96 (3H, s), 4.06 (2H, d, J=7.2 Hz), 7.01 (1H, d, J=8.6 Hz), 7.67 (1H,dd, J=2.2, 8.6 Hz), 7.72 (1H, s), 7.86 (1H, d, J=2.2 Hz).

Example 77

[0724] Preparation of6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[0725] Following the procedure of Example 4,6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield the title compoundas a colorless crystalline powder (yield: 67.5%).

[0726] Melting point: 235.8-236.7° C.

[0727]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.25-2.32(1H, m), 2.77 (3H, s), 3.15 (4H, br), 3.36 (4H, br), 3.88 (2H, s), 3.93(3H, s), 4.01 (2H, d, J=7.0 Hz), 7.26 (1H, d, J=8.6 Hz), 7.83 (1H, dd,J=2.2, 8.6 Hz), 7.91 (1H, d, J=2.2 Hz), 8.12 (1H, s).

[0728] IR (KBr) cm⁻¹: 1653, 1608, 1507, 1289, 1064.

[0729] Mass m/z: 404 (M⁺), 406 (M⁺).

Example 78

[0730] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one

[0731] Following the procedure of Example 1 (10),6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-one and diethanolamine were reacted to yield thetitle compound as a yellow oil (yield: 79.6%).

[0732]¹H NMR (400 MHz, CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 2.28-2.39 (1H,m), 2.71 (4H, t, J=4.9 Hz), 3.66 (4H, t, J=4.9 Hz), 3.70 (2H, s), 3.94(3H, s), 4.07 (2H, d, J=7.4 Hz), 6.98 (1H, d, J=8.8 Hz), 7.68 (1H, dd,J=1.8, 8.7 Hz), 7.72 (1H, s), 7.85 (1H, d, J=2.1 Hz).

Example 79

[0733] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one hydrochloride

[0734] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-chloro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the titlecompound as a colorless crystalline powder (yield: 60.1%).

[0735] Melting point: 153.0-153.5° C.

[0736]¹H NMR (400 MHz, DMSO-d₆) δ: 0.95 (6H, d, J=6.6 Hz), 2.23-2.34(1H, m), 3.34 (4H, t, J=5.1 Hz), 3.83 (4H, t, J=5.1 Hz), 3.94 (3H, s),4.04 (2H, d, J=7.1 Hz), 4.44 (2H, s), 7.28 (1H, d, J=8.8 Hz), 7.85 (1H,dd, J=2.4, 8.6 Hz), 7.94 (1H, d, J=2.4 Hz), 8.45 (1H, s).

[0737] IR (KBr) cm⁻¹: 1652, 1607, 1508, 1421, 1293, 1062.

[0738] Mass m/z: 391 (M⁺-H₂O)

Example 80

[0739] Preparation of6-(3-chloro-4-methoxyphenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

[0740] Following the procedure of Example 7,6-(3-chloro-4-methoxyphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as ayellow oil (yield: 84.8%).

[0741]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.31-2.39 (1H,m), 2.35 (6H, s), 3.50 (2H, s), 3.95 (3H, s), 4.07 (2H, d, J=7.2 Hz),6.99 (1H, d, J=8.6 Hz), 7.70 (1H, dd, J=1.4, 8.6 Hz), 7.88 (1H, d, J=1.4Hz).

Example 81

[0742] Preparation of6-(3-chloro-4-methoxyphenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-onehydrochloride

[0743] Following the procedure of Example 4,6-(3-chloro-4-methoxyphenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one was reacted to yield the title compound as a whitesolid (yield: 69.4%).

[0744] Melting point: 213.6-214.3° C.

[0745]¹H NMR (400 MHz, DMSO-d₆) δ: 0.95 (6H, d, J=6.8 Hz), 2.22-2.34(1H, m), 2.81 (6H, s), 3.94 (3H, s), 4.04 (2H, d, J=7.1 Hz), 4.27 (2H,s), 7.28 (1H, d, J=8.8 Hz), 7.87 (1H, dd, J=2.2, 8.8 Hz), 7.95 (1H, d,J=2.2 Hz), 8.53 (1H, s).

[0746] IR (KBr) cm⁻¹: 1652, 1608, 1508, 1289, 1064.

[0747] Mass m/z: 349 (M⁺), 351 (M⁺)

Example 82

[0748] Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[0749] 1) Preparation of ethyl2-ethoxycarbonyl-4-(4-fluoro-3-methylphenyl)-2-hydroxy-4-oxobutanoate

[0750] Following the procedure of Example 1 (3),5-acetyl-2-fluorotoluene was reacted to yield the title compound as paleyellow prisms (yield: 95.9%).

[0751]¹H NMR (400 MHz, CDCl₃) δ: 1.30 (6H, t, J=7.1 Hz), 2.33 (3H, d,J=1.7 Hz), 3.79 (2H, s) 4.29 (1H, s), 4.31 (4H, q, J=7.1 Hz), 7.08 (1H,dd, J=8.8, 8.8 Hz), 7.78-7.85 (2H, m).

[0752] 2) Preparation of4-carboxy-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-on e

[0753] Following the procedure of Example 1 (4), ethyl2-ethoxycarbonyl-4-(4-fluoro-3-methylphenyl)-2-hydroxy-4-ox o-butanoatewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 88.9%).

[0754] Melting point: 213.6-214.3° C.

[0755]¹H NMR (400 MHz, DMSO-d₆) δ: 2.51 (3H, d, J=1.7 Hz), 7.26 (1H, dd,J=9.1, 9.1 Hz), 7.77-7.81 (1H, m), 7.89 (1H, d, J=7.3 Hz), 8.49 (1H, s),13.99 (1H, br).

[0756] 3) Preparation of6-(4-fluoro-3-methylphenyl)-4-methoxy-carbonyl-2H-pyrid azin-3-one

[0757] Following the procedure of Example 1 (5),4-carboxy-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted toyield the title compound as a pale yellow crystalline powder (yield:76.8%).

[0758]¹H NMR (400 MHz, CDCl₃) δ: 2.35 (3H, d, J=2.0 Hz), 3.99 (3H, s),7.10 (1H, dd, J=8.9, 8.9 Hz), 7.58-7.62 (1H, m), 7.60 (1H, d, J=7.3 Hz),8.31 (1H, s).

[0759] 4) Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

[0760] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-2-methoxycarbonyl-2H-pyridazin-3-one wasreacted to yield the title compound as pale yellow prisms (yield:86.3%).

[0761] Melting point: 71.4-73.8° C.

[0762]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.31-2.42 (1H,m), 2.35 (3H, d, J=2.0 Hz), 3.98 (3H, s), 4.12 (2H, d, J=7.3 Hz), 7.10(1H, dd, J=8.8, 8.8 Hz), 7.57-7.65 (2H, m), 8.21 (1H, s).

[0763] 5) Preparation of4-carboxy-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyr idazin-3-one

[0764] Following the procedure of Example 1 (7),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:90.0%).

[0765] Melting point: 129.3-132.1° C.

[0766]¹H NMR (400 MHz, CDCl₃) δ: 1.02 (6H, d, J=6.8 Hz), 2.33-2.44 (1H,m), 2.37 (3H, d, J=2.0 Hz), 4.21 (2H, d, J=7.3 Hz), 7.13 (1H, dd, J=8.8,8.8 Hz), 7.64-7.71 (2H, m), 8.63 (1H, s).

[0767] IR (KBr) cm⁻¹: 1742, 1636, 1537, 1422.

[0768] Mass m/z: 304 (M⁺).

[0769] 6) Preparation of6-(4-fluoro-3-methylphenyl)-4-hydroxy-methyl-2-isobutyl-2H-pyridazin-3-one

[0770] Following the procedure of Example 1 (8),4-carboxy-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridaz in-3-one wasreacted to yield the title compound as colorless needles (yield: 24.7%).

[0771] Melting point: 107.4-110.4° C.

[0772]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.29-2.40 (1H,m), 2.35 (3H, d, J=1.7 Hz), 3.14 (1H, t, J=5.9 Hz), 4.08 (2H, d, J=7.6Hz), 4.71 (2H, d, J=5.9 Hz), 7.08 (1H, dd, J=8.8, 8.8 Hz), 7.56-7.65(3H, m).

[0773] IR (KBr) cm⁻¹: 3401, 1658, 1648, 1618, 1602, 1501.

[0774] Mass m/z: 290 (M⁺).

[0775] 7) Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[0776] Following the procedure of Example 1 (9),6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one was reacted to yield the title compound as colorlessneedles (yield: 91.4%).

[0777] Melting point: 114.6-117.1° C.

[0778]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.29-2.40 (1H,m), 2.36 (3H, s), 3.17 (3H, s), 4.08 (2H, d, J=7.6 Hz), 5.27 (2H, d,J=1.5 Hz), 7.09 (1H, dd, J=8.9, 8.9 Hz), 7.56-7.69 (2H, m), 7.75 (1H, t,J=1.5 Hz).

[0779] IR (KBr) cm⁻¹: 1656, 1611, 1505, 1354, 1166.

[0780] Mass m/z: 368 (M⁺).

[0781] 8) Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[0782] Following the procedure of Example 1 (10),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as aslightly yellow oil (yield: 79.1%).

[0783]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.27-2.40 (1H,m), 2.32 (3H, s), 2.36 (3H, d, J=2.0 Hz), 2.51 (4H, br), 2.62 (4H, br),3.58 (2H, d, J=1.5 Hz), 4.07 (2H, d, J=7.3 Hz), 7.09 (1H, dd, J=8.8, 8.8Hz), 7.58 (1H, ddd, J=2.0, 4.9, 8.8 Hz), 7.64 (1H, dd, J=2.0, 7.3 Hz),7.73 (1H, t, J=1.5 Hz).

[0784] IR (Neat) cm⁻¹: 1652, 1609, 1503.

[0785] Mass m/z: 372 (M⁺).

Example 83

[0786] Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[0787] Following the procedure of Example 4,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield the title compoundas colorless prisms (yield: 95.9%).

[0788] Melting point: 234.8-237.4° C. (dec.)

[0789]¹H NMR (400 MHz, DMSO-d₆) δ: 0.93 (6H, d, J=6.8 Hz), 2.19-2.30(1H, m), 2.32 (3H, d, J=2.0 Hz), 2.81 (3H, s), 2.89-3.62 (10H, brm),4.00 (2H, d, J=7.3 Hz), 7.29 (1H, dd, J=9.0, 9.0 Hz), 7.72-7.78 (1H, m),7.83 (1H, dd, J=2.4, 7.6 Hz), 8.31 (1H, brs).

[0790] IR (KBr) cm⁻¹: 1660, 1609, 1504.

Example 84

[0791] Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methylaminomethyl-2H-pyridazin-3-one

[0792] Following the procedure of Example 9 (4),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as apale yellow oil (yield: 96.2%).

[0793]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 1.65 (1H, br),2.29-2.42 (1H, m), 2.34 (3H, d, J=1.7 Hz), 2.51 (3H, s), 3.77 (2H, d,J=1.2 Hz), 4.07 (2H, d, J=7.3 Hz), 7.07 (1H, dd, J=8.8, 8.8 Hz),7.54-7.63 (2H, m), 7.64 (1H, t, J=1.2 Hz).

[0794] IR (Neat) cm⁻¹: 3306, 1653, 1605, 1507.

[0795] Mass m/z: 303 (M⁺)

Example 85

[0796] Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methylaminomethyl-2H-pyridazin-3-one hydrochloride

[0797] Following the procedure of Example 4,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methylaminomethyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless prisms (yield:86.6%).

[0798] Melting point: 196.8-199.7° C.

[0799]¹H NMR (400 MHz, DMSO-d₆) δ: 0.93 (6H, d, J=6.8 Hz), 2.19-2.31(1H, m), 2.32 (3H, s), 2.65 (3H, s), 4.02 (2H, d, J=7.3 Hz), 4.12 (2H,s), 7.31 (1H, dd, J=8.5, 8.5 Hz), 7.72-7.78 (1H, m), 7.80-7.85 (1H, m),8.32 (1H, s).

[0800] IR (KBr) cm⁻¹: 2722, 1652, 1615, 1505.

Example 86

[0801] Preparation of4-(4-benzyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

[0802] Following the procedure of Example 1 (10),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-oneand 1-benzylpiperazine were reacted to yield the title compound as apale yellow oil (yield: 98.6%).

[0803]¹H NMR (400 MHz, CDCl₃) δ: 0.97 (6H, d, J=6.8 Hz), 2.29-2.39 (1H,m), 2.36 (3H, d, J=1.7 Hz), 2.55 (4H, br), 2.61 (4H, br), 3.55 (2H, s),3.57 (2H, d, J=1.2 Hz), 4.06 (2H, d, J=7.6 Hz), 7.09 (1H, dd, J=8.9, 8.9Hz), 7.23-7.34 (5H, m), 7.51 (1H, ddd, J=2.4, 4.8, 8.9 Hz), 7.63 (1H,dd, J=2.4, 7.2 Hz), 7.72 (1H, s).

[0804] IR (Neat) cm⁻¹: 1652, 1608, 1505.

[0805] Mass m/z: 448 (M⁺).

Example 87

[0806] Preparation of4-(4-benzyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one dihydrochloride

[0807] Following the procedure of Example 4,4-(4-benzyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:95.3%).

[0808] Melting point: 259.1-263.1° C. (dec.)

[0809]¹H NMR (400 MHz, DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.17-2.29(1H, m), 2.32 (3H, s), 2.55 (4H, br), 3.23-3.56 (8H, brm), 4.00 (2H, d,J=7.3 Hz), 4.11 (2H, brs), 4.38 (2H, brs), 7.29 (1H, dd, J=9.0, 9.0 Hz),7.43-7.48 (3H, m), 7.59-7.65 (2H, m), 7.72-7.77 (1H, m), 7.79-7.84 (1H,m), 8.35 (1H, brs).

[0810] IR (KBr) cm⁻¹: 1660, 1618, 1612, 1453.

Example 88

[0811] Preparation of4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

[0812] Following the procedure of Example 7,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as aslightly yellow oil (yield: 96.4%).

[0813]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.28-2.39 (1H,m), 2.35 (3H, d, J=2.2 Hz), 2.56 (6H, s), 3.50 (2H, d, J=1.2 Hz), 4.07(2H, d, J=7.3 Hz), 7.07 (1H, dd, J=8.9, 8.9 Hz), 7.59-7.67 (2H, m), 7.74(1H, t, J=1.2 Hz).

[0814] IR (Neat) cm⁻¹: 1652, 1608, 1506.

[0815] Mass m/z: 317 (M⁺).

Example 89

[0816] Preparation of4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one hydrochloride

[0817] Following the procedure of Example 4,4-dimethyl-aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the title compound ascolorless needles (yield: 97.2%).

[0818] Melting point: 208.5-213.0° C.

[0819]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.19-2.30(1H, m), 2.32 (3H, s), 2.81 (6H, s), 4.03 (2H, d, J=7.0 Hz), 4.30 (2H,s), 7.30 (1H, dd, J=9.0, 9.0 Hz), 7.74-7.80 (1H, m), 7.85 (1H, m), 8.51(1H, s).

[0820] IR (KBr) cm⁻¹: 1648, 1608, 1507.

Example 90

[0821] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

[0822] Following the procedure of Example 1 (10),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as aslightly yellow oil (yield: 91.5%).

[0823]¹H NMR (400 MHz, CDCl₃) δ: 0.97 (6H, d, J=6.8 Hz), 2.27-2.40 (1H,m), 2.34 (3H, d, J=2.0 Hz), 2.70 (4H, t, J=5.0 Hz), 3.66 (4H, d, J=5.0Hz), 3.69 (2H, s), 3.91 (2H, br), 4.07 (2H, d, J=7.6 Hz), 7.07 (1H, dd,J=8.9, 8.9 Hz), 7.60 (1H, ddd, J=2.2, 5.1, 8.9 Hz), 7.64 (1H, dd, J=2.2,7.3 Hz), 7.71 (1H, s).

[0824] IR (Neat) cm⁻¹: 3391, 1654, 1371, 1505.

[0825] Mass m/z: 359 (M⁺-H₂O).

Example 91

[0826] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one hydrochloride

[0827] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the titlecompound as slightly yellow needles (yield: 92.4%).

[0828] Melting point: 155.1-157.3° C.

[0829]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.20-2.31(1H, m), 2.32 (3H, d, J=1.2 Hz), 3.35 (4H, br, overlapped with H₂O),3.82 (4H, br), 4.02 (2H, d, J=7.3 Hz), 4.50 (2H, s), 5.37 (2H, br), 7.30(1H, dd, J=9.0, 9.0 Hz), 7.78 (1H, ddd, J=2.0, 4.9, 9.0 Hz), 7.85 (1H,dd, J=2.0, 7.3 Hz), 7.71 (1H, s).

[0830] IR (KBr) cm⁻¹: 3281, 1655, 1606.

Example 92

[0831] Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(piperidino)methyl-2H-pyridazin-3-one

[0832] 6-(4-Fluoro-3-methylphenyl)-2-isobutyl-4-methane-sulfonyloxymethyl-2H-pyridazin-3-one (80 mg, 0.22 mmol) and piperidine (55mg, 0.65 mmol) were dissolved in ethanol (0.5 mL), and the mixture washeated at 80° C. for 1 hour under stirring. The solvent was distilledoff. The residue was purified by preparative thin-layer chromatographyon silica gel [developing solvent: chloroform/methanol (10/1)] to yieldthe title compound as a slightly yellow oil (73 mg, 94.0%).

[0833]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.9 Hz), 1.45-1.53 (2H,m), 1.61-1.68 (4H, m), 2.28-2.41 (1H, m), 2.36 (3H, d, J=2.0 Hz),2.47-2.53 (4H, m) 3.52 (2H, d, J=1.5 Hz), 4.07 (2H, d, J=7.3 Hz), 7.08(1H, dd, J=8.9, 8.9 Hz), 7.59 (1H, ddd, J=1.7, 4.9, 8.9 Hz), 7.65 (1H,dd, J=1.7, 7.3 Hz), 7.76 (1H, t, J=1.5 Hz).

[0834] IR (Neat) cm⁻¹: 1652, 1616, 1506.

[0835] Mass m/z: 357 (M⁺).

Example 93

[0836] Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(piperidino)methyl-2H-pyridazin-3-one hydrochloride

[0837] Following the procedure of Example 4,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(piperidino)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow prisms(yield: 90.7%).

[0838]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 1.34-1.47(1H, m), 1.64-1.73 (1H, m), 1.74-1.83 (4H, m), 2.20-2.30 (1H, m), 2.32(3H, s), 2.95-3.02 (2H, m), 3.36-3.45 (1H, m), 4.02 (2H, d, J=7.3 Hz),4.25 (2H, d, J=5.1 Hz), 7.30 (1H, dd, J=9.0, 9.0 Hz), 7.75-7.80 (1H, m),7.83-7.87 (1H, m), 8.59 (1H, s).

[0839] IR (KBr) cm⁻¹: 2532, 1652, 1616, 1505, 1433.

Example 94

[0840] Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(morpholino)methyl-2H-pyridazin-3-one

[0841] Following the procedure of Example 92,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and morpholine were reacted to yield the titlecompound as a slightly yellow oil (yield: 97.4%).

[0842]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.28-2.41 (1H,m), 2.36 (3H, d, J=2.0 Hz), 2.58 (4H, t, J=4.6 Hz), 3.57 (2H, d, J=1.2Hz), 3.78 (4H, t, J=4.6 Hz), 4.07 (2H, d, J=7.3 Hz), 7.09 (1H, dd,J=8.8, 8.8 Hz), 7.58 (1H, ddd, J=2.0, 4.9, 8.8 Hz), 7.64 (1H, dd, J=2.0,7.3 Hz), 7.75 (1H, t, J=1.5 Hz).

[0843] IR (Neat) cm⁻¹: 1659, 1606, 1503.

[0844] Mass m/z: 359 (M⁺)

Example 95

[0845] Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(morpholino)methyl-2H-pyridazin-3-one hydrochloride

[0846] Following the procedure of Example 4,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(morpholino)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless prisms (yield:92.4%).

[0847] Melting point: 215.4-216.6° C.

[0848]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.19-2.30(1H, m), 2.32 (3H, s), 3.21 (2H, br), 3.79-3.98 (6H, m), 4.02 (2H, d,J=7.3 Hz), 4.33 (2H, brs), 7.30 (1H, dd, J=9.0, 9.0 Hz), 7.74-7.79 (1H,m), 7.81-7.86 (1H, m), 8.56 (1H, brs).

[0849] IR (KBr) cm⁻¹: 2392, 1647, 1607.

Example 96

[0850] Preparation of4-aminomethyl-6-(4-fluoro-3-methyl-phenyl)-2-isobutyl-2H-pyridazin-3-one

[0851] 1) Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-one

[0852] Following the procedure of Example 24 (1),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 93.7%).

[0853] Melting point: 181.2-187.2° C.

[0854]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.29-2.40 (1H,m), 2.30 (3H, s), 4.07 (2H, d, J=7.3 Hz), 4.91 (2H, s), 7.01 (1H, dd,J=9.0, 9.0 Hz), 7.31 (1H, s), 7.41-7.46 (1H, m), 7.50-7.53 (1H, m),7.76-7.81 (2H, m), 7.90-7.95 (2H, m).

[0855] IR (KBr) cm⁻¹: 1720, 1656, 1619, 1611.

[0856] Mass m/z: 419 (M⁺).

[0857] 2) Preparation of4-aminomethyl-6-(4-fluoro-3-methyl-phenyl)-2-isobutyl-2H-pyridazin-3-one

[0858] Following the procedure of Example 24 (2),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly yellow oil (yield:99.6%).

[0859]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 1.64 (2H, br),2.30-2.40 (1H, m), 2.35 (3H, d, J=2.0 Hz), 3.89 (2H, d, J=1.2 Hz), 4.07(2H, d, J=7.3 Hz), 7.07 (1H, dd, J=8.8, 8.8 Hz), 7.60 (1H, ddd, J=2.1,4.9, 8.8 Hz), 7.64 (1H, dd, J=2.1, 7.4 Hz), 7.67 (1H, t, J=1.2 Hz).

[0860] IR (Neat) cm⁻¹: 3372, 3301, 1655, 1605, 1504.

[0861] Mass m/z: 289 (M⁺).

Example 97

[0862] Preparation of4-aminomethyl-6-(4-fluoro-3-methyl-phenyl)-2-isobutyl-2H-pyridazin-3-onehydrochloride

[0863] Following the procedure of Example 4,4-aminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyr idazin-3-onewas reacted to yield the title compound as colorless needles (yield:79.8%).

[0864] Melting point: 217.5-220.5° C. (dec.)

[0865]¹H NMR (400 MHz, DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.20-2.30(1H, m), 2.32 (3H, d, J=1.7 Hz), 4.01 (2H, d, J=2.2 Hz), 4.02 (2H, d,J=7.3 Hz), 7.31 (1H, dd, J=9.0, 9.0 Hz), 7.75 (1H, ddd, J=2.1, 4.9, 9.0Hz), 7.83 (1H, dd, J=2.1, 7.4 Hz), 8.28 (1H, s).

[0866] IR (KBr) cm⁻¹: 2960, 2927, 2872, 1656, 1614, 1507.

Example 98

[0867] Preparation of4-diethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

[0868] Following the procedure of Example 9 (4),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethylamine were reacted to yield thetitle compound as a slightly yellow oil (yield: 94.7%).

[0869]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 1.07 (6H, t,J=7.1 Hz), 2.30-2.41 (1H, m), 2.35 (3H, d, J=11.5 Hz), 2.61 (4H, q,J=7.1 Hz), 3.60 (2H, d, J=1.7 Hz), 4.08 (2H, d, J=7.5 Hz), 7.08 (1H, dd,J=8.9, 8.9 Hz), 7.60 (1H, ddd, J=2.2, 4.9, 8.9 Hz), 7.65 (1H, dd, J=2.2,7.3 Hz), 7.85 (1H, t, J=1.5 Hz).

[0870] IR (Neat) cm⁻¹: 1652, 1609, 1506.

[0871] Mass m/z: 345 (M⁺).

Example 99

[0872] Preparation of4-diethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one hydrochloride

[0873] Following the procedure of Example 4,4-diethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 70.1%).

[0874] Melting point: 154.3-157.3° C.

[0875]¹H NMR (400 MHz, CDCl₃) δ: 0.92 (6H, d, J=6.8 Hz), 1.29 (6H, t,J=7.2 Hz), 2.20-2.30 (1H, m), 2.32 (3H, d, J=1.2 Hz), 3.09-3.25 (4H, m),4.03 (2H, d, J=7.3 Hz), 4.28 (2H, d, J=5.6 Hz), 7.30 (1H, dd, J=9.0, 9.0Hz), 7.80 (1H, ddd, J=2.0, 4.9, 9.0 Hz), 7.87 (1H, dd, J=2.0, 7.3 Hz),7.85 (1H, t, J=1.5 Hz).

[0876] IR (KBr) cm⁻¹: 2559, 2491, 1652, 1613, 1507.

Example 100

[0877] Preparation of4-(4-tert-butoxycarbonyl-1-pierazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one

[0878] Following the procedure of Example 1 (10),6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxy-methyl-2H-pyridazin-3-oneand tert-butyl 1-piperazine-carboxylate were reacted to yield the titlecompound as a slightly yellow oil (yield: 97.5%).

[0879]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.46 (9H, s),2.28-2.40 (1H, m), 2.36 (3H, d, J=1.7 Hz), 3.50 (4H, t, J=4.9 Hz), 3.58(2H, d, J=1.0 Hz), 4.08 (2H, d, J=7.3 Hz), 7.09 (1H, dd, J=8.9, 8.9 Hz),7.58 (1H, ddd, J=2.0, 4.9, 8.9 Hz), 7.63 (1H, dd, J=2.0, 7.3 Hz), 7.75(1H, s).

[0880] IR (Neat) cm⁻¹: 1695, 1652, 1608, 1506.

Example 101

[0881] Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

[0882] Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-pierazinyl)methyl-6-(4-fluoro-3-methyl-phenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow oil (yield:quantitative).

[0883]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 1.47 (1H, br),2.28-2.40 (1H, m), 2.36 (3H, d, J=1.7 Hz), 2.56 (4H, t, J=4.9 Hz), 2.97(4H, t, J=4.9 Hz), 3.56 (2H, d, J=1.4 Hz), 4.07 (2H, d, J=7.3 Hz), 7.09(1H, dd, J=8.8, 8.8 Hz), 7.58 (1H, ddd, J=2.0, 4.9, 8.8 Hz), 7.64 (1H,dd, J=2.0, 7.3 Hz), 7.75 (1H, t, J=1.4 Hz).

Example 102

[0884] Preparation of6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[0885] Following the procedure of Example 4,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield the title compound as paleyellow prisms (yield: 87.2%).

[0886] Melting point: 154.9-158.0° C.

[0887]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.8 Hz), 2.19-2.30(1H, m), 2.32 (3H, d, J=11.7 Hz), 3.04 (4H, br), 3.71 (4H, br), 4.01(2H, d, J=7.3 Hz), 7.28 (1H, dd, J=8.8, 8.8 Hz), 7.76 (1H, ddd, J=2.0,4.9, 8.8 Hz), 7.83 (1H, dd, J=2.0, 7.3 Hz), 8.40 (1H, brs).

[0888] IR (KBr) cm⁻¹: 1659, 1610, 1504, 1422.

Example 103

[0889] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

[0890] 1) Preparation of ethyl4-(3,4-difluorophenyl)-2-ethoxy-carbonyl-2-hydroxy-4-ox obutanoate

[0891] Following the procedure of Example 1 (3),3′,4′-difluoroacetophenone was reacted to yield the title compound as apale yellow oil (yield: 81.6%).

[0892]¹H NMR (400 MHz, CDCl₃) δ: 1.30 (6H, t, J=7.1 Hz), 3.78 (2H, s),4.22 (1H, s), 4.31 (4H, q, J=7.1 Hz), 7.24-7.30 (1H, m), 7.73-7.82 (2H,m).

[0893] IR (Neat) cm⁻¹: 3483, 1740, 1695, 1612.

[0894] Mass m/z: 312 (M⁺-H₂O).

[0895] 2) Preparation of4-carboxy-6-(3,4-difluorophenyl)-2H-pyridazin-3-one

[0896] Following the procedure of Example 1 (4), ethyl4-(3,4-difluorophenyl)-2-ethoxycarbonyl-2-hydroxy-4-oxo-but anoate wasreacted to yield the title compound as a pale yellow crystalline powder(yield: 88.9%).

[0897] 3) Preparation of4-methoxycarbonyl-6-(3,4-difluorophenyl)-2H-pyridazin-3-one

[0898] Following the procedure of Example 1 (5),4-carboxy-6-(3,4-difluorophenyl)-2H-pyridazin-3-one was reacted to yieldthe title compound as a pale yellow crystalline powder (yield: 85.8%).

[0899]¹H NMR (400 MHz, CDCl₃) δ: 4.01 (3H, s), 7.25-7.32 (1H, m),7.53-7.57 (1H, m), 7.67-7.73 (1H, m), 8.31 (1H, s), 11.70 (1H, br).

[0900] IR (KBr) cm⁻¹: 3223, 3159, 1722, 1676, 1659.

[0901] Mass m/z: 266 (M⁺)

[0902] 4) Preparation of6-(3,4-difluorophenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

[0903] Following the procedure of Example 1 (6),6-(3,4-difluorophenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reactedto yield the title compound as a yellow oil (yield: quantitative).

[0904]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.30-2.41 (1H,m), 3.98 (3H, s), 4.13 (2H, d, J=7.2 Hz), 7.23-7.30 (1H, m), 7.49-7.55(1H, m), 7.68 (1H, ddd, J=2.2, 7.6, 11.1 Hz), 8.20 (1H, s).

[0905] 5) Preparation of4-carboxy-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazi n-3-one

[0906] Following the procedure of Example 1 (7),6-(3,4-difluorophenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyri dazin-3-onewas reacted to yield the title compound as colorless fine needles(yield: 91.4%).

[0907] Melting point: 163.4-163.7° C.

[0908]¹H NMR (400 MHz, CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 2.33-2.43 (1H,m), 4.22 (2H, d, J=7.4 Hz), 7.27-7.35 (1H, m), 7.56-7.62 (1H, m), 7.74(1H, ddd, J=2.4, 7.6, 11.2 Hz), 8.62 (1H, s), 14.05 (1H, s).

[0909] IR (KBr) cm⁻¹: 3436, 1737, 1635, 1522, 1434, 1276, 1102, 806.

[0910] Mass m/z: 308 (M⁺)

[0911] 6) Preparation of6-(3,4-difluorophenyl)-4-hydroxymethyl-2-isobutyl-2H-py ridazin-3-one

[0912] Following the procedure of Example 1 (8),4-carboxy-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one wasreacted to yield the title compound as colorless fine-needles (yield:25.0%).

[0913]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.29-2.39 (1H,m), 2.96 (1H, t, J=5.9 Hz), 4.08 (2H, d, J=7.4 Hz), 4.72 (2H, dd, J=1.2,5.8 Hz), 7.22-7.28 (1H, m), 7.51-7.55 (1H, m), 7.64-7.71 (2H, m).

[0914] 7) Preparation of6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[0915] Following the procedure of Example 1 (9),6-(3,4-difluorophenyl)-4-hydroxymethyl-2-isobutyl-2H-pyrida zin-3-onewas reacted to yield the title compound as colorless fine-needles(yield: 81.4%).

[0916] Melting point: 113.3-113.4° C.

[0917]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.27-2.40 (1H,m), 3.18 (3H, s), 4.08 (2H, d, J=7.4 Hz), 5.28 (2H, d, J=1.6 Hz),7.23-7.30 (1H, m), 7.50-7.54 (1H, m), 7.68 (1H, ddd, J=2.2, 7.6, 11.1Hz), 7.75 (1H, t, J=1.4 Hz).

[0918] IR (KBr) cm⁻¹: 3447, 1656, 1613, 1522, 1354, 1167, 1049, 877.

[0919] Mass m/z: 372 (M⁺)

[0920] 8) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

[0921] Following the procedure of Example 1 (10),6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reactedto yield the title compound as a yellow oil (yield: 85.5%).

[0922]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.47 (9H, s),2.28-2.38 (1H, m), 2.52 (4H, t, J=4.7 Hz), 3.51 (4H, t, J=4.7 Hz), 3.58(2H, s), 4.07 (2H, d, J=7.2 Hz), 7.21-7.29 (1H, m), 7.50-7.55 (1H, m),7.64-7.71 (1H, m), 7.76 (1H, d, J=1.0 Hz).

Example 104

[0923] Preparation of6-(3,4-difluorophenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[0924] Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the titlecompound as a white solid (yield: 72.5%).

[0925] Melting point: 182.5-186.0° C.

[0926]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.22-2.33(1H, m), 3.11 (4H, br), 3.30 (4H, t, J=5.1 Hz), 3.90 (2H, s), 4.02 (2H,d, J=7.1 Hz), 7.52 (1H, ddd, J=8.6, 8.6, 10.5 Hz), 7.73-7.78 (1H, m),7.90 (1H, ddd, J=2.2, 8.0, 11.7 Hz), 8.20 (1H, s).

[0927] IR (KBr) cm⁻¹: 1656, 1609, 1522, 1436, 1276, 1112.

[0928] Mass m/z: 362 (M⁺)

Example 105

[0929] Preparation of6-(3,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[0930] Following the procedure of Example 1 (10),6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield thetitle compound as a yellow oil (yield: 79.1%).

[0931]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.28-2.39 (1H,m), 2.34 (3H, s), 2.55 (4H, br), 2.63 (4H, br), 3.58 (2H, s), 4.07 (2H,d, J=7.2 Hz), 7.22-7.29 (1H, m), 7.50-7.57 (1H, m), 7.64-7.72 (1H, m),7.74 (1H, s).

Example 106

[0932] Preparation of6-(3,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[0933] Following the procedure of Example 4,6-(3,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 70.3%).

[0934] Melting point: 242.5-243.4° C.

[0935]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.8 Hz), 2.22-2.33(1H, m), 2.77 (3H, s), 3.11 (4H, br), 3.34 (4H, br), 3.84 (2H, s), 4.02(2H, d, J=7.1 Hz), 7.52 (1H, ddd, J=8.6, 8.6, 10.5 Hz), 7.72-7.77 (1H,m), 7.89 (1H, ddd, J=2.2, 7.9, 11.7 Hz), 8.12 (1H, s).

[0936] IR (KBr) cm⁻¹: 1652, 1607, 1522, 1435, 1278.

[0937] Mass m/z: 376 (M⁺)

Example 107

[0938] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

[0939] Following the procedure of Example 1 (10),6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethanolamine were reacted to yield the titlecompound as a yellow oil (yield: 75.8%).

[0940]¹H NMR (400 MHz, CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 2.25-2.38 (1H,m), 2.70 (4H, br), 3.64-3.70 (6H, m), 4.06 (2H, d, J=7.4 Hz), 7.15-7.25(1H, m), 7.54-7.58 (1H, m), 7.67-7.73 (1H, m), 7.88 (1H, s).

Example 108

[0941] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one hydrochloride

[0942] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as a white solid (yield: 70.3%).

[0943] Melting point: 127.5-128.3° C.

[0944]¹H NMR (400 MHz, DMSO₆) δ: 0.95 (6H, d, J=6.8 Hz), 2.23-2.34 (1H,m), 3.35 (4H, t, J=5.1 Hz), 3.84 (4H, t, J=5.1 Hz), 4.05 (2H, d, J=7.1Hz), 4.45 (2H, s), 7.54 (1H, ddd, J=8.6, 8.6, 10.5 Hz), 7.76-7.81 (1H,m), 7.93 (1H, ddd, J=2.2, 7.8, 12.0 Hz), 8.53 (1H, s).

[0945] IR (KBr) cm⁻¹: 1653, 1604, 1521, 1437, 1275.

[0946] Mass m/z: 363 (M⁺-H₂O)

Example 109

[0947] Preparation of6-(3,4-difluorophenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-one

[0948] Following the procedure of Example 7,6-(3,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as a yellowoil (yield: 85.5%).

[0949]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.29-2.40 (1H,m), 2.35 (6H, s), 3.50 (2H, s), 4.07 (2H, d, J=7.4 Hz), 7.20-7.30 (1H,m), 7.53-7.60 (1H, m), 7.67-7.73 (1H, m), 7.74 (1H, s).

Example 110

[0950] Preparation of6-(3,4-difluorophenyl)-4-dimethyl-aminomethyl-2-isobutyl-2H-pyridazin-3-one hydrochloride

[0951] Following the procedure of Example 4,6-(3,4-difluorophenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow flakes(yield: 85.9%).

[0952] Melting point: 226.5-227.7° C.

[0953]¹H NMR (400 MHz, DMSO-d₆) δ: 0.96 (6H, d, J=6.8 Hz), 2.23-2.34(1H, m), 2.81 (6H, s), 4.05 (2H, d, J=7.1 Hz), 4.28 (2H, s), 7.54(ddd,J=8.7, 8.7, 10.5 Hz), 7.76-7.81 (1H, m), 7.93 (1H, ddd, J=2.2, 7.9, 12.0Hz), 8.57 (1H, s).

[0954] IR (KBr) cm⁻¹: 1648, 1607, 1525, 1437, 1288, 1112.

[0955] Mass m/z: 321 (M⁺)

Example 111

[0956] Preparation of4-aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-py ridazin-3-one

[0957] 1) Preparation of ethyl4-(2,4-difluorophenyl)-2-ethoxy-carbonyl-2-hydroxy-4-ox obutanoate

[0958] Following the procedure of Example 1 (3),2′,4′-difluoroacetophenone was reacted to yield the title compound as apale yellow oil (yield: 76.8%).

[0959]¹H NMR (400 MHz, CDCl₃) δ: 1.30 (6H, t, J=7.1 Hz), 3.81 (2H, d,J=3.4 Hz), 4.18 (1H, s), 4.30 (4H, q, J=7.1 Hz), 6.90 (1H, ddd, J=2.4,8.5, 10.0 Hz), 6.94-7.00 (1H, m), 7.94 (1H, ddd, J=6.6, 8.5, 8.5 Hz).

[0960] IR (Neat) cm⁻¹: 3491, 1743, 1692, 1612.

[0961] Mass m/z: 312 (M⁺-H₂O)

[0962] 2) Preparation of4-carboxy-6-(2,4-difluorophenyl)-2H-pyridazin-3-one

[0963] Following the procedure of Example 1 (4), ethyl4-(2,4-difluorophenyl)-2-ethoxycarbonyl-2-hydroxy-4-oxo-but anoate wasreacted to yield the title compound as a pale yellow crystalline powder(yield: 95.2%).

[0964] 3) Preparation of6-(2,4-difluorophenyl)-4-methoxycarbonyl-2H-pyridazin-3 one

[0965] Following the procedure of Example 1 (5),4-carboxy-6-(2,4-difluorophenyl)-2H-pyridazin-3-one was reacted to yieldthe title compound as a pale yellow crystalline powder (yield: 81.2%).

[0966]¹H NMR (400 MHz, CDCl₃) δ: 3.99 (3H, s), 6.96 (1H, ddd, J=2.4,8.8, 10.1 Hz), 6.99-7.04 (1H, m), 7.77 (1H, ddd, J=6.3, 8.8, 8.8 Hz),8.30 (1H, d, J=2.0 Hz), 12.05 (1H, br).

[0967] IR (KBr) cm⁻¹: 3217, 3148, 1721, 1673, 1611.

[0968] Mass m/z: 266 (M⁺).

[0969] 4) Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyridazin-3-one

[0970] Following the procedure of Example 1 (6),6-(2,4-difluorophenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reactedto yield the title compound as a pale yellow oil (yield: 84.8%).

[0971]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.29-2.42 (1H,m), 3.97 (3H, s), 4.12 (2H, d, J=7.3 Hz), 6.94 (1H, ddd, J=2.4, 8.8,11.2 Hz), 6.98-7.04 (1H, m), 7.73 (1H, ddd, J=6.3, 6.3, 8.8 Hz), 8.18(1H, d, J=2.0 Hz).

[0972] IR (Neat) cm⁻¹: 1755, 1748, 1668, 1620, 1506.

[0973] Mass m/z: 322 (M⁺).

[0974] 5) Preparation of4-carboxy-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazi n-3-one

[0975] Following the procedure of Example 1 (7),6-(2,4-difluorophenyl)-2-isobutyl-4-methoxycarbonyl-2H-pyri dazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 92.7%).

[0976] Melting point: 126.5-128.2° C.

[0977]¹H NMR (400 MHz, CDCl₃) δ: 1.02 (6H, d, J=6.6 Hz), 2.31-2.43 (1H,m), 4.22 (2H, d, J=7.6 Hz), 6.96-7.07 (2H, m), 7.74 (1H, ddd, J=6.3,6.3, 8.8 Hz), 8.61 (1H, d, J=2.2 Hz), 14.02 (1H, s).

[0978] IR (KBr) cm⁻¹: 1739, 1636, 1618, 1573, 1465.

[0979] Mass m/z: 308 (M⁺).

[0980] 6) Preparation of6-(2,4-difluorophenyl)-4-hydroxymethyl-2-isobutyl-2H-py ridazin-3-one

[0981] Following the procedure of Example 1 (8),4-carboxy-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one wasreacted to yield the title compound as a pale yellow oil (yield: 45.0%).

[0982]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.27-2.40 (1H,m), 3.15 (1H, t, J=6.1 Hz), 4.08 (2H, d, J=7.3 Hz), 4.69 (2H, dd, J=1.2,6.1 Hz), 6.93 (1H, ddd, J=2.4, 8.8, 11.2 Hz), 6.96-7.02 (1H, m),7.61-7.63 (1H, m), 7.72 (1H, ddd, J=6.3, 6.3, 8.8 Hz).

[0983] IR (Neat) cm⁻¹: 3412, 1652, 1620, 1507.

[0984] Mass m/z: 294 (M⁺).

[0985] 7) Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[0986] Following the procedure of Example 1 (9),6-(2,3-difluorophenyl)-4-hydroxymethyl-2-isobutyl-2H-pyrida zin-3-onewas reacted to yield the title compound as colorless needles (yield:96.3%).

[0987] Melting point: 86.7-88.6° C.

[0988]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.26-2.39 (1H,m), 3.16 (3H, s), 4.08 (2H, d, J=7.3 Hz), 5.26 (2H, d, J=1.2 Hz), 6.94(1H, ddd, J=2.4, 8.8, 11.2 Hz), 6.97-7.03 (1H, m), 7.71 (1H, ddd, J=6.3,6.3, 8.8 Hz), 7.73-7.75 (1H, m).

[0989] IR (KBr) cm⁻¹: 1659, 1612, 1508, 1359, 1166.

[0990] Mass m/z: 372 (M⁺).

[0991] 8) Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-phthalimidomethyl-2H-pyridazin-3-one

[0992] Following the procedure of Example 24 (1),6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the title compound ascolorless needles (yield: 91.1%).

[0993] Melting point: 152.3-155.6° C.

[0994]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.28-2.39 (1H,m), 4.07 (2H, d, J=7.3 Hz), 4.89 (2H, d, J=1.0 Hz), 6.83 (1H, ddd,J=2.4, 8.8, 11.0 Hz), 6.91-6.97 (1H, m), 7.27-7.31 (1H, m), 7.66 (1H,ddd, J=6.3, 6.3, 8.8 Hz), 7.74-7.80 (2H, m), 7.86-7.94 (2H, m).

[0995] IR (KBr) cm⁻¹: 1773, 1720, 1650, 1617, 1509, 1418, 1389.

[0996] Mass m/z: 423 (M⁺).

[0997] 9) Preparation of4-aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyri dazin-3-one

[0998] Following the procedure of Example 24 (2),2-isobutyl-6-(2,4-difluorophenyl)-4-phthalimidomethyl-2H-pyridazin-3-one was reacted to yield the title compound as a slightlyyellow oil (yield: 98.4%).

[0999]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 1.66 (2H, br),2.24-2.41 (1H, m), 3.87 (2H, s), 4.08 (2H, d, J=7.3 Hz), 6.92 (1H, ddd,J=2.4, 8.8, 11.2 Hz), 6.97-7.02 (1H, m), 7.63 (1H, t, J=1.1 Hz), 7.71(1H, ddd, J=6.3, 6.3, 8.8 Hz).

[1000] IR (Neat) cm⁻¹: 3381, 3307, 1652, 1611, 1508.

[1001] Mass m/z: 293 (M⁺).

Example 112

[1002] Preparation of4-aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-py ridazin-3-onehydrochloride

[1003] Following the procedure of Example 4,4-aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazi n-3-one wasreacted to yield the title compound as slightly yellow needles (yield:94.9%).

[1004] Melting point: 161.4-163.9° C.

[1005]¹H NMR (400 MHz, DMSO-d₆) δ: 0.93 (6H, d, J=6.8 Hz), 2.18-2.34(1H, m), 4.01 (2H, s), 4.02 (2H, d, J=7.3 Hz), 7.24-7.31 (1H, m), 7.46(1H, ddd, J=2.4, 8.8, 11.5 Hz), 7.76 (1H, ddd, J=6.3, 6.3, 8.8 Hz), 7.95(1H, s).

[1006] IR (KBr) cm⁻¹: 1652, 1616, 1597, 1509.

Example 113

[1007] Preparation of6-(2,4-difluorophenyl)-4-dimethyl-aminomethyl-2-isobutyl-2H-pyridazin-3-one

[1008] Following the procedure of Example 7,6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as aslightly yellow oil (yield: 94.1%).

[1009]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 2.27-2.38 (1H,m), 2.34 (6H, s), 3.49 (2H, d, J=1.5 Hz), 4.07 (2H, d, J=7.6 Hz), 6.92(1H, ddd, J=2.4, 8.8, 11.2 Hz), 6.95-7.01 (1H, m), 7.70 (1H, t, J=1.5Hz), 7.71 (1H, ddd, J=6.3, 6.3, 8.8 Hz).

[1010] IR (Neat) cm⁻¹: 1652, 1612, 1508.

[1011] Mass m/z: 321 (M⁺).

Example 114

[1012] Preparation of6-(2,4-difluorophenyl)-4-dimethyl-aminomethyl-2-isobutyl-2H-pyridazin-3-one hydrochloride

[1013] Following the procedure of Example 4,6-(2,4-difluorophenyl)-4-dimethylaminomethyl-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow prisms (yield:89.8%).

[1014] Melting point: 170.1-173.5° C.

[1015]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.8 Hz), 2.18-2.29(1H, m), 2.80 (6H, s), 4.03 (2H, d, J=7.3 Hz), 4.30 (2H, s), 7.25-7.31(1H, m), 7.45 (1H, ddd, J=2.4, 8.8, 11.2 Hz), 7.81 (1H, ddd, J=6.3, 6.3,8.8 Hz). 8.15 (1H, d, J=1.7 Hz),

[1016] IR (KBr) cm⁻¹: 1648, 1612, 1523, 1510.

Example 115

[1017] Preparation of4-diethylaminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

[1018] Following the procedure of Example 9 (4),6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethylamine were reacted to yield the titlecompound as a pale yellow oil (yield: quantitative).

[1019]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 1.06 (6H, t,J=7.1 Hz), 2.27-2.39 (1H, m), 2.59 (4H, q, J=7.1 Hz), 3.59 (2H, d, J=1.7Hz), 4.07 (2H, d, J=7.3 Hz), 6.92 (1H, ddd, J=2.4, 8.8, 11.2 Hz),6.95-7.01 (1H, m), 7.72 (1H, ddd, J=6.3, 6.3, 8.8 Hz), 7.83 (1H, td,J=1.5, 2.9 Hz).

[1020] IR (Neat) cm⁻¹: 1656, 1613, 1508.

[1021] Mass m/z: 349 (M⁺).

Example 116

[1022] Preparation of4-diethylaminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one hydrochloride

[1023] Following the procedure of Example 4,4-diethylamino-methyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:80.9%).

[1024] Melting point: 128.9-131.7° C.

[1025]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.8 Hz), 1.28 (6H, t,J=7.2 Hz), 2.18-2.29 (1H, m), 3.10-3.23 (4H, m), 4.03 (2H, d, J=7.3 Hz),4.29 (2H, d, J=5.4 Hz), 7.28 (1H, ddd, J=2.2, 8.8, 8.8 Hz), 7.45 (1H,ddd, J=2.2, 8.8, 8.8 Hz), 7.81 (1H, ddd, J=6.3, 8.8, 8.8 Hz), 8.24 (1H,d, J=1.5 Hz).

Example 117

[1026] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

[1027] Following the procedure of Example 1 (10),6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethanolamine were reacted to yield the titlecompound as a slightly yellow oil (yield: 97.6%).

[1028]¹H NMR (400 MHz, CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 2.26-2.40 (1H,m), 2.70 (4H, t, J=5.0 Hz), 3.65 (4H, t, J=5.0 Hz), 3.70 (2H, s), 4.09(2H, d, J=7.3 Hz), 6.92 (1H, ddd, J=2.7, 8.8, 11.2 Hz), 6.97-7.03 (1H,m), 7.63 (1H, d, J=2.4 Hz), 7.75 (1H, ddd, J=6.3, 6.3, 8.8 Hz).

[1029] IR (Neat) cm⁻¹: 3401, 1648, 1597, 1508.

[1030] Mass m/z: 363 (M⁺-H₂O).

Example 118

[1031] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one hydrochloride

[1032] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow prisms(yield: 89.0%).

[1033] Melting point: 161.8-163.9° C.

[1034]¹H NMR (400 MHz, DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.18-2.29(1H, m), 3.27-3.40 (4H, br, overlapped with H₂O), 3.76-3.84 (4H, m),4.03 (2H, d, J=7.3 Hz), 4.51 (2H, brs), 5.34 (2H, br), 7.24-7.31 (1H,m), 7.41-7.48 (1H, m), 7.76-7.84 (1H, m), 8.15 (1H, m).

[1035] IR (KBr) cm⁻¹: 3233, 3172, 1645, 1613, 1593, 1421.

Example 119

[1036] Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1037] Following the procedure of Example 1 (10),6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield thetitle compound as a pale yellow oil (yield: 94.0%).

[1038]¹H NMR (400 MHz, CDCl₃) δ: 0.97 (6H, d, J=6.6 Hz), 2.28-2.38 (1H,m), 2.31 (3H, s), 2.50 (4H, br), 2.61 (4H, br), 3.57 (2H, d, J=1.5 Hz),4.07 (2H, d, J=7.3 Hz), 6.93 (1H, ddd, J=2.4, 8.8, 11.2 Hz 6.96-7.02(1H, m), 7.69-7.75 (2H, m).

[1039] IR (Neat) cm⁻¹: 1655, 1616, 1596, 1508.

[1040] Mass m/z: 376 (M⁺).

Example 120

[1041] Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[1042] Following the procedure of Example 4,6-(2,4-difluorophenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:90.4%).

[1043] Melting point: 248.1-251.7° C. (dec.).

[1044]¹H NMR (400 MHz, DMSO-d₆, 100° C.) δ: 0.93 (6H, d, J=6.8 Hz),2.20-2.29 (1H, m), 2.76 (3H, s), 3.09 (4H, br, overlapped with H₂O),3.27 (4H, br), 3.74 (2H, s), 4.00 (2H, d, J=7.1 Hz), 7.14-7.29 (2H, m),7.71-7.79 (2H, m).

[1045] IR (KBr) cm⁻¹: 1652, 1612, 1514.

Example 121

[1046] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one

[1047] Following the procedure of Example 1 (10),6-(2,4-difluorophenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate were reactedto yield the title compound as a slightly yellow oil (yield: 97.5%).

[1048]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 1.47 (9H, s),2.28-2.39 (1H, m), 2.52 (4H, t, J=4.9 Hz), 3.49 (4H, t, J=4.9 Hz), 3.57(2H, d, J=1.2 Hz), 4.07 (2H, d, J=7.3 Hz), 6.93 (1H, ddd, J=2.4, 8.8,11.2 Hz), 6.96-7.02 (1H, m), 7.69-7.75 (2H, m).

[1049] IR (Neat) cm⁻¹: 1695, 1655, 1613, 1508, 1425.

[1050] Mass m/z: 462 (M⁺)

Example 122

[1051] Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

[1052] Following the procedure of Example 20,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(2,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one was reacted to yield the titlecompound as a yellow oil (yield: quantitative).

[1053]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.8 Hz), 1.81 (1H, br),2.27-2.39 (1H, m), 2.50-2.56 (4H, brm), 2.94 (4H, t, J=4.8 Hz), 3.54(2H, d, J=1.2 Hz), 4.07 (2H, d, J=7.3 Hz), 6.93 (1H, ddd, J=2.4, 8.8,11.2 Hz), 6.94-7.02 (1H, m), 7.69-7.76 (2H, m).

[1054] IR (Neat) cm⁻¹: 3314, 1655, 1613, 1508.

[1055] Mass m/z: 362 (M⁺)

Example 123

[1056] Preparation of6-(2,4-difluorophenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[1057] Following the procedure of Example 4,6-(2,4-difluorophenyl)-2-isobutyl-4-(1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly yellow crystallinepowder (yield: 90.8%).

[1058] Melting point: 136.3-140.9° C.

[1059]¹H NMR (400 MHz, DMSO-d₆) δ: 0.93 (6H, d, J=6.6 Hz), 2.20-2.30(1H, m), 2.95 (4H, t, J=5.0 Hz), 3.02 (4H, t, J=5.0 Hz), 3.76 (2H, s),4.00 (2H, d, J=7.3 Hz), 7.14-7.20 (1H, m), 7.26 (1H, ddd, J=2.7, 8.8,11.2 Hz), 7.86 (1H, ddd, J=6.6, 6.6, 8.8 Hz), 7.81 (1H, s).

[1060] IR (KBr) cm⁻¹: 1656, 1616, 1597, 1509, 1426.

Example 124

[1061] Preparation of2-benzyl-4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1062] 1) Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

[1063] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one andbenzyl chloride were reacted to yield the title compound as yellowneedles (yield: 71.0%).

[1064] Melting point: 109.0-110.5° C.

[1065]¹H NMR (400 MHz, CDCl₃) δ: 2.35 (3H, d, J=1.7 Hz), 3.96 (3H, s),5.44 (2H, s), 7.10 (1H, dd, J=8.8, 8.8 Hz), 7.28-7.37 (3H, m), 7.52 (2H,d, J=6.3 Hz), 7.57-7.64 (2H, m), 8.21 (1H, s).

[1066] IR (KBr) cm⁻¹: 1750, 1744, 1657, 1278, 1233, 1123.

[1067] Mass m/z: 352 (M⁺).

[1068] 2) Preparation of2-benzyl-4-carboxy-6-(4-fluoro-3-methyl-phenyl)-2H-pyri dazin-3-one

[1069] Following the procedure of Example 1 (7),2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellowcrystalline powder (yield: 65.2%).

[1070] Melting point: 191.2-192.3° C.

[1071]¹H NMR (400 MHz, CDCl₃) δ: 2.37 (3H, d, J=2.0 Hz), 5.52 (2H, s),7.13 (1H, dd, J=8.8, 8.8 Hz), 7.33-7.41 (3H, m), 7.48-7.52 (2H, m),7.64-7.70 (2H, m) 8.62 (1H, s), 14.01 (1H, br).

[1072] IR (KBr) cm⁻¹: 1739, 1633, 1569, 1457, 1423, 1240.

[1073] Mass m/z: 338 (M⁺).

[1074] 3) Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1075] Following the procedure of Example 1 (8),2-benzyl-4-carboxy-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one wasreacted to yield the title compound as slightly yellow needles (yield:28.4%).

[1076] Melting point: 119.5-120.6° C.

[1077]¹H NMR (400 MHz, CDCl₃) δ: 2.34 (3H, d, J=1.7 Hz), 3.01 (1H, t,J=5.9 Hz), 4.70 (2H, dd, J=1.2, 5.9 Hz), 5.41 (2H, s), 7.08 (1H, dd,J=8.8, 8.8 Hz), 7.27-7.37 (3H, m), 7.48 (1H, d, J=6.6 Hz), 7.57-7.65(2H, m) 7.66 (1H, t, J=1.2 Hz).

[1078] IR (KBr) cm⁻¹: 3330, 1657, 1643, 1611, 1597, 1506, 1239.

[1079] Mass m/z: 324 (M⁺).

[1080] 4) Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1081] Following the procedure of Example 1 (9),2-benzyl-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyr idazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 98.9%).

[1082] Melting point: 147.6-148.3° C.

[1083]¹H NMR (400 MHz, CDCl₃) δ: 2.35 (3H, d, J=2.0 Hz), 3.15 (3H, s),5.26 (2H, d, J=1.2 Hz), 5.41 (2H, s), 7.09 (1H, dd, J=8.8, 8.8 Hz),7.27-7.37 (3H, m), 7.47 (2H, d, J=6.6 Hz), 7.62 (1H, d, J=7.3 Hz),7.57-7.60 (1H, m), 7.75 (1H, s).

[1084] IR (KBr) cm⁻¹: 1656, 1617, 1507, 1355, 1168, 1033, 879.

[1085] Mass m/z: 402 (M⁺).

[1086] 5) Preparation of2-benzyl-4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1087] Following the procedure of Example 1 (10),2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate werereacted to yield the title compound as a yellow oil (yield: 91.8%).

[1088]¹H NMR (400 MHz, CDCl₃) δ: 1.46 (9H, s), 2.35 (3H, d, J=1.8 Hz),2.50 (4H, t, J=4.9 Hz), 3.49 (4H, t, J=4.9 Hz), 3.56 (2H, d, J=1.4 Hz),5.40 (2H, s), 7.26-7.36 (4H, m), 7.49 (2H, d, J=6.6 Hz), 7.55-7.60 (1H,m), 7.63 (1H, dd, J=1.8, 7.2 Hz), 7.74 (1H, s).

Example 125

[1089] Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[1090] Following the procedure of Example 2,2-benzyl-4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 60.9%).

[1091] Melting point: 162.7-180.7° C. (dec.)

[1092]¹H NMR (400 MHz, DMSO-d₆) δ: 2.31 (3H, d, J=2.0 Hz), 3.09 (4H,br), 3.28 (4H, t, J=5.2 Hz), 3.89 (2H, s), 5.36 (2H, s), 7.21-7.40 (6H,m), 7.70-7.76 (1H, m), 7.79 (1H, dd, J=1.7, 7.3 Hz), 8.16 (1H, s).

[1093] IR (KBr) cm⁻¹: 1656, 1607, 1505, 1239, 1126, 700.

[1094] Mass m/z: 392 (M⁺)

Example 126

[1095] Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1096] Following the procedure of Example 1 (10),2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield thetitle compound as a yellow oil (yield: 81.3%).

[1097]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, s), 2.36 (3H, d, J=1.8 Hz),2.53 (4H, br), 2.61 (4H, br), 3.57 (2H, d, J=1.4 Hz), 5.40 (2H, s), 7.08(1H, t, J=8.9 Hz), 7.26-7.36 (3H, m), 7.49 (2H, d, J=6.8 Hz), 7.56-7.60(1H, m), 7.64 (1H, dd, J=1.8, 7.2 Hz), 7.73 (1H, s).

Example 127

[1098] Preparation of2-benzyl-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[1099] Following the procedure of Example 4,2-benzyl-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield the title compound asa colorless crystalline powder (yield: 78.6%).

[1100] Melting point: 240.0-242.5° C. (dec.)

[1101]¹H NMR (400 MHz, DMSO-d₆) δ: 2.31 (3H, d, J=1.7 Hz), 2.76 (3H, s),3.10 (4H, br), 3.33 (4H, br), 3.84 (2H, s), 5.36 (2H, s), 7.21-7.39 (6H,m), 7.69-7.74 (1H, m), 7.78 (1H, dd, J=2.1, 7.8 Hz), 8.09 (1H, s).

[1102] IR (KBr) cm⁻¹: 1653, 1607, 1504, 1454, 1240, 1127.

[1103] Mass m/z: 406 (M⁺)

Example 128

[1104] Preparation of2-benzyl-4-N,N-bis(2-hydroxyethyl)-aminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1105] Following the procedure of Example 1 (10),2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethanolamine were reacted to yield thetitle compound as a yellow oil (yield: 87.6%).

[1106]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, s), 2.69 (4H, t, J=4.9 Hz),3.64 (4H, t, J=5.0 Hz), 3.68 (2H, s), 5.40 (2H, s), 7.06 (1H, t, J=8.9Hz), 7.26-7.38 (3H, m), 7.45 (2H, d, J=7.0 Hz), 7.58-7.68 (2H, m), 7.75(1H, s).

Example 129

[1107] Preparation of2-benzyl-4-N,N-bis(2-hydroxyethyl)-aminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one hydrochloride

[1108] Following the procedure of Example 4,2-benzyl-4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 75.9%).

[1109] Melting point: 161.7-163.0° C.

[1110]¹H NMR (400 MHz, DMSO-d₆) δ: 2.31 (2H, d, J=2.0 Hz), 3.34 (4H, t,J=5.2 Hz), 3.83 (4H, t, J=5.4 Hz), 4.47 (2H, s), 5.39 (2H, s), 7.23-7.40(6H, m), 7.73-7.77 (1H, m), 7.82 (1H, dd, J=1.7, 7.3 Hz), 8.47 (1H, s).

[1111] IR (KBr) cm⁻¹: 1602, 1503, 1239, 1088.

[1112] Mass m/z: 393 (M⁺-H₂O)

Example 130

[1113] Preparation of2-benzyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1114] Following the procedure of Example 7,2-benzyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield thetitle compound as a yellow oil (yield: 92.7%).

[1115]¹H NMR (400 MHz, CDCl₃) δ: 2.34 (9H, s), 3.49 (2H, s), 5.40 (2H,s), 7.06 (1H, t, J=8.9 Hz), 7.25-7.35 (3H, m), 7.49 (2H, d, J=7.4 Hz),7.58-7.67 (2H, m), 7.75 (1H, s).

Example 131

[1116] Preparation of2-benzyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one hydrochloride

[1117] Following the procedure of Example 4,2-benzyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as colorless flakes (yield:72.6%).

[1118] Melting point: 225.3-226.0° C.

[1119]¹H NMR (400 MHz, DMSO-d₆) δ: 2.31 (3H, d, J=2.0 Hz), 2.81 (6H, s),4.28 (2H, s), 5.39 (2H, s), 7.21-7.41 (6H, m), 7.73-7.78 (1H, m), 7.83(1H, dd, J=2.2, 7.6 Hz), 8.52 (1H, s).

[1120] IR (KBr) cm⁻¹: 1652, 1610, 1506, 1240, 1126, 702.

[1121] Mass m/z: 351 (M⁺)

Example 132

[1122] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1123] 1) Preparation of2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

[1124] Following the procedure of Example 1 (6),6-(3-fluoro-4-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one andcinnamyl bromide were reacted to yield the title compound as pale yellowneedles (yield: 58.7%).

[1125] Melting point: 95.9-96.7° C.

[1126]¹H NMR (400 MHz, CDCl₃) δ: 2.35 (3H, d, J=1.7 Hz), 3.99 (3H, s),5.04 (2H, dd, J=1.2, 6.8 Hz), 6.45 (1H, dt, J=15.9, 6.8 Hz), 6.75 (1H,d, J=15.9 Hz), 7.10 (1H, dd, J=8.9, 8.9 Hz), 7.20-7.33 (3H, m), 7.39(2H, d, J=7.1 Hz), 7.58-7.66 (2H, m), 8.23 (1H, s).

[1127] IR (KBr) cm⁻¹: 1724, 1661, 1603, 1501, 1292, 1234, 1123.

[1128] Mass m/z: 378 (M⁺).

[1129] 2) Preparation of4-carboxy-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyr idazin-3-one

[1130] Following the procedure of Example 1 (7),2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:85.1%).

[1131] Melting point: 142.8-143.6° C.

[1132]¹H NMR (400 MHz, CDCl₃) δ: 2.36 (3H, d, J=2.0 Hz), 5.12 (2H, dd,J=1.2, 6.8 Hz), 6.42 (1H, dt, J=15.9, 6.8 Hz), 6.80 (1H, d, J=15.9 Hz),7.13 (1H, dd, J=8.8, 8.8 Hz), 7.22-7.36 (3H, m), 7.40-7.43 (2H, m),7.65-7.72 (2H, m), 8.64 (1H, s), 14.04 (1H, br).

[1133] IR (KBr) cm⁻¹: 3438, 3061, 2688, 1747, 1637, 1567, 1463, 1244.

[1134] Mass m/z: 364 (M⁺)

[1135] 3) Preparation of2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1136] Following the procedure of Example 1 (8),4-carboxy-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridaz in-3-one wasreacted to yield the title compound as slightly yellow needles (yield:20.1%).

[1137] Melting point: 139.9-140.9° C.

[1138]¹H NMR (400 MHz, CDCl₃) δ: 2.34 (3H, d, J=1.5 Hz), 3.00 (1H, br),4.73 (2H, s), 5.01 (2H, d, J=6.6 Hz), 6.44 (1H, dt, J=15.9, 6.6 Hz),6.72 (2H, d, J=15.9 Hz), 7.08 (1H, dd, J=8.9, 8.9 Hz), 7.24 (1H, t,J=7.3 Hz), 7.30 (2H, dd, J=7.3, 7.3 Hz), 7.39 (2H, d, J=7.3 Hz),7.58-7.62 (1H, m), 7.64 (1H, d, J=7.3 Hz), 7.67 (1H, s).

[1139] IR (KBr) cm⁻¹: 3393, 1655, 1648, 1602, 1505, 1451, 1238, 1077.

[1140] Mass m/z: 350 (M⁺).

[1141] 4) Preparation of2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1142] Following the procedure of Example 1 (9),2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as colorlessneedles (yield: 91.9%).

[1143] Melting point: 78.4-80.5° C.

[1144]¹H NMR (400 MHz, CDCl₃) δ: 2.35 (3H, d, J=2.0 Hz), 3.17 (3H, s),5.10 (2H, dd, J=1.2, 6.8 Hz), 5.28 (2H, d, J=1.2 Hz), 6.42 (1H, dt,J=15.9, 6.8 Hz), 6.73 (1H, d, J=15.9 Hz), 7.09 (1H, dd, J=8.9, 8.9 Hz),7.21-7.33 (3H, m), 7.40 (2H, d, J=8.8 Hz), 7.57-7.62 (1H, m), 7.64 (1H,d, J=8.8 Hz), 7.77 (1H, t, J=1.3 Hz).

[1145] IR (KBr) cm⁻¹: 1663, 1612, 1508, 1355, 1241, 1167, 988, 958, 873.

[1146] Mass m/z: 428 (M⁺).

[1147] 5) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1148] Following the procedure of Example 1 (10),2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate werereacted to yield the title compound as a yellow oil (yield: 86.7%).

[1149]¹H NMR (400 MHz, CDCl₃) δ: 1.47 (9H, s), 2.35 (3H, d, J=1.6 Hz),2.52 (4H, t, J=5.0 Hz), 3.51 (4H, t, J=4.9 Hz), 3.59 (2H, d, J=1.4 Hz),5.00 (2H, dd, J=1.0, 6.6 Hz), 6.45 (1H, dt, J=15.8, 6.6 Hz), 6.72 (1H,d, J=15.8 Hz), 7.08 (1H, dd, J=8.9, 8.9 Hz), 7.22 (1H, t, J=7.2 Hz),7.29 (2H, dd, J=7.0, 7.0 Hz), 7.38 (2H, d, J=7.7 Hz), 7.56-7.61 (1H, m),7.65 (1H, dd, J=1.8, 7.2 Hz), 7.77 (1H, s).

Example 133

[1150] Preparation of2-cinnamyl-6-(4-fluoro-3-methyl-phenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[1151] Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 96.0%).

[1152] Melting point: 171.1-187.1° C. (dec.)

[1153]¹H NMR (400 MHz, DMSO-d₆) δ: 2.31 (3H, d, J=2.0 Hz), 3.21 (4H, t,J=4.9 Hz), 3.34 (4H, t, J=5.1 Hz), 3.99 (2H, s), 4.95 (2H, dd, J=1.3,6.4 Hz), 6.45 (1H, dt, J=16.1, 6.3 Hz), 6.68 (1H, d, J=16.1 Hz),7.20-7.26 (2H, m), 7.29-7.34 (2H, m), 7.41-7.45 (2H, m), 7.73-7.79 (1H,m), 7.83 (1H, dd, J=1.7, 7.3 Hz), 8.26 (1H, s).

[1154] IR (KBr) cm⁻¹: 1656, 1605, 1505, 1239, 962.

[1155] Mass m/z: 418 (M⁺)

Example 134

[1156] Preparation of2-cinnamyl-6-(4-fluoro-3-methyl-phenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1157] Following the procedure of Example 1 (10),2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yieldthe title compound as a yellow oil (yield: 80.1%).

[1158]¹H NMR (400 MHz, CDCl₃) δ: 2.32 (3H, s), 2.35 (3H, d, J=1.8 Hz),2.51 (4H, br), 2.62 (4H, br), 3.59 (2H, d, J=1.4 Hz), 4.99 (2H, dd,J=1.1, 6.6 Hz), 6.45 (1H, dt, J=15.8, 6.0 Hz), 6.72 (1H, d, J=15.8 Hz),7.08 (1H, dd, J=8.9, 8.9 Hz), 7.22 (1H, tt, J=1.6, 7.2 Hz), 7.29 (2H,dd, J=7.2, 7.2 Hz), 7.39 (2H, dd, J=1.4, 7.2 Hz), 7.56-7.61 (1H, m),7.65 (1H, dd, J=1.8, 7.2 Hz), 7.75 (1H, t, J=1.4 Hz)

Example 135

[1159] Preparation of2-cinnamyl-6-(4-fluoro-3-methyl-phenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[1160] Following the procedure of Example 4,2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield the title compoundas a colorless crystalline powder (yield: 66.3%).

[1161] Melting point: 236.1-237.1° C.

[1162]¹H NMR (400 MHz, DMSO-d₆) δ: 2.32 (3H, d, J=2.2 Hz), 2.76 (3H, s),3.08 (4H, br), 3.32 (4H, br), 3.83 (2H, s), 4.94 (2H, dd, J=1.2, 6.4Hz), 6.45 (1H, dt, J=16.1, 6.3 Hz), 6.67 (1H, d, J=15.8 Hz), 7.19-7.26(2H, m), 7.29-7.34 (2H, m), 7.41-7.44 (2H, m), 7.71-7.76 (1H, m), 7.81(1H, dd, J=2.2, 7.6 Hz), 8.07 (1H, s).

[1163] IR (KBr) cm⁻¹: 1652, 1607, 1505, 1239, 1129.

[1164] Mass m/z: 432 (M⁺)

Example 136

[1165] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1166] Following the procedure of Example 1 (10),2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethanolamine were reacted to yield thetitle compound as a yellow oil (yield: 83.7%).

[1167]¹H NMR (400 MHz, CDCl₃) δ: 2.32 (3H, s), 2.69 (4H, t, J=4.9 Hz),3.65 (4H, d, J=4.9 Hz), 3.69 (2H, s), 4.98 (2H, d, J=6.6 Hz), 6.41 (1H,dt, J=15.8, 6.5 Hz), 6.68 (1H, d, J=15.8 Hz), 7.05 (1H, dd, J=8.9, 8.9Hz), 7.21 (1H, t, J=7.2 Hz), 7.28 (2H, dd, J=7.2, 7.2 Hz), 7.37 (2H, d,J=7.6 Hz), 7.58-7.63 (1H, m), 7.66 (1H, dd, J=1.8, 7.2 Hz), 7.81 (1H,s).

Example 137

[1168] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cinnamyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onehydrochloride

[1169] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cinnamyl-6-(4-fluoro-3-methyl-phenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 63.2%).

[1170] Melting point: 112.5-113.2° C.

[1171]¹H NMR (400 MHz, DMSO-d₆) δ: 2.32 (3H, d, J=1.9 Hz), 3.35 (4H, t,J=5.1 Hz), 3.84 (4H, t, J=5.1 Hz), 4.46 (2H, s), 4.98 (2H, dd, J=1.5,6.1 Hz), 6.45 (1H, dt, J=15.8, 6.1 Hz), 6.69 (1H, d, J=16.0 Hz),7.21-7.27 (2H, m), 7.29-7.34 (2H, m), 7.41-7.44 (2H, m), 7.757.80 (1H,m), 7.85 (1H, dd, J=2.0, 7.3 Hz), 8.47 (1H, s).

[1172] IR (KBr) cm⁻¹: 1652, 1604, 1505, 1241, 971.

[1173] Mass m/z: 419 (M⁺-H₂O)

Example 138

[1174] Preparation of2-cinnamyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1175] Following the procedure of Example 7,2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield thetitle compound as a yellow oil (yield: 90.9%).

[1176]¹H NMR (400 MHz, CDCl₃) δ: 2.34 (3H, d, J=2.0 Hz), 2.36 (6H, s),3.51 (2H, d, J=1.4 Hz), 5.00 (2H, dd, J=1.3, 6.8 Hz), 6.46 (1H, dt,J=15.8, 6.6 Hz), 6.72 (1H, d, J=15.8 Hz), 7.07 (1H, dd, J=8.9, 8.9 Hz),7.22 (1H, tt, J=1.4, 7.2 Hz), 7.29 (2H, dd, J=7.2, 7.2 Hz), 7.39 (2H,dd, J=1.6, 7.0 Hz), 7.60-7.65 (1H, m), 7.67 (1H, dd, J=2.2, 7.2 Hz),7.76 (1H, s).

Example 139

[1177] Preparation of2-cinnamyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one hydrochloride

[1178] Following the procedure of Example 4,2-cinnamyl-4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 81.1%).

[1179] Melting point: 183.6-184.5° C.

[1180]¹H NMR (400 MHz, DMSO-d₆) δ: 2.32 (3H, d, J=2.0 Hz), 2.83 (6H, s),4.29 (2H, s), 4.98 (2H, dd, J=1.3, 6.4 Hz), 6.46 (1H, dt, J=16.1, 6.3Hz), 6.69 (1H, d, J=16.1 Hz), 7.22-7.27 (2H, m), 7.297.35 (2H, m),7.41-7.44 (2H, m), 7.76-7.81 (1H, m), 7.86 (1H, dd, J=2.2, 7.3 Hz), 8.50(1H, s).

[1181] IR (KBr) cm⁻¹: 1652, 1607, 1505, 1240, 965.

[1182] Mass m/z: 377 (M⁺)

Example 140

[1183] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazi n-3-one

[1184] 1) Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

[1185] Following the procedure of Example 1 (6),6-(3-fluoro-4-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and4-chlorocinnamyl chloride were reacted to yield the title compound asyellow needles (yield: 71.7%).

[1186] Melting point: 137.8-138.8° C.

[1187]¹H NMR (400 MHz, CDCl₃) δ: 2.35 (3H, d, J=1.7 Hz), 3.99 (3H, s),5.03 (2H, d, J=6.6 Hz), 6.43 (1H, dt, J=15.6, 6.6 Hz), 6.70 (1H, d,J=15.6 Hz), 7.10 (1H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz), 7.31 (2H, d,J=8.8 Hz), 7.58-7.63 (1H, m), 7.64 (1H, dd, J=2.1, 7.0 Hz), 8.24 (1H,s).

[1188] IR (KBr) cm⁻¹: 1724, 1709, 1667, 1506, 1291, 1236, 1126, 831.

[1189] Mass m/z: 412 (M⁺), 414 (M⁺).

[1190] 2) Preparation of4-carboxy-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1191] Following the procedure of Example 1 (7),2-(4-chloro-cinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as ayellow crystalline powder (yield: 86.2%).

[1192] Melting point: 186.0-186.6° C.

[1193]¹H NMR (400 MHz, CDCl₃) δ: 2.36 (3H, d, J=2.0 Hz), 5.11 (2H, dd,J=1.2, 6.8 Hz), 6.39 (1H, dt, J=15.9, 6.8 Hz), 6.75 (1H, d, J=15.6 Hz),7.13 (1H, dd, J=8.8, 8.8 Hz), 7.29 (2H, d, J=8.5 Hz), 7.33 (2H, d, J=8.5Hz), 7.65-7.71 (2H, m), 8.64 (1H, s), 13.98 (1H, br).

[1194] IR (KBr) cm⁻¹: 3471, 1738, 1631, 1566, 1490, 1467, 1403, 1242,812, 802.

[1195] Mass m/z: 398 (M⁺), 400 (M⁺).

[1196] 3) Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1197] Following the procedure of Example 1 (8),4-carboxy-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 17.2%).

[1198] Melting point: 131.8-133.1° C.

[1199]¹H NMR (400 MHz, CDCl₃) δ: 2.34 (3H, d, J=2.0 Hz), 4.73 (2H, d,J=1.2 Hz), 4.99 (2H, dd, J=1.0, 6.6 Hz), 6.40 (1H, dt, J=15.9, 6.6 Hz),6.75 (1H, d, J=15.9 Hz), 7.08 (1H, dd, J=8.9, 8.9 Hz), 7.26 (2H, d,J=8.8 Hz), 7.31 (2H, d, J=8.8. Hz), 7.57-7.62 (1H, m), 7.64 (1H, dd,J=2.2, 7.3 Hz), 7.69 (1H, t, J=1.2 Hz).

[1200] IR (KBr) cm⁻¹: 3359, 1653, 1598, 1506, 1492, 1240, 1091, 1076.

[1201] Mass m/z: 384 (M⁺), 386 (M⁺)

[1202] 4) Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1203] Following the procedure of Example 1 (9),2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxy-methyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless needles (yield:94.9%).

[1204] Melting point: 117.8-119.5° C.

[1205]¹H NMR (400 MHz, CDCl₃) δ: 2.35 (3H, d, J=2.0 Hz), 3.17 (3H, s),4.99 (2H, dd, J=1.2, 6.6 Hz), 5.28 (2H, d, J=1.2 Hz), 6.38 (1H, dt,J=15.9, 6.6 Hz), 6.75 (1H, d, J=15.9 Hz), 7.10 (1H, dd, J=8.8, 8.8 Hz),7.27 (2H, d, J=8.5 Hz), 7.32 (2H, d, J=8.5. Hz), 7.57-7.65 (2H, m), 7.78(1H, t, J=1.3 Hz).

[1206] IR (KBr) cm⁻¹: 1663, 1619, 1506, 1492, 1346, 1240, 1172, 960,830.

[1207] Mass m/z: 462 (M⁺), 464 (M⁺)

[1208] 5) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methyl-phenyl)-2H-pyridazin-3-one

[1209] Following the procedure of Example 1 (10),2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 87.9%).

[1210]¹H NMR (400 MHz, CDCl₃) δ: 1.47 (9H, s), 2.35 (3H, d, J=1.6 Hz),2.52 (4H, t, J=4.9 Hz), 3.50 (4H, t, J=5.0 Hz), 3.59 (2H, d, J=1.2 Hz),4.99 (2H, dd, J=1.0, 6.6 Hz), 6.42 (1H, dt, J=15.8, 6.6 Hz), 6.67 (1H,d, J=16.0 Hz), 7.09 (1H, dd, J=8.9, 8.9 Hz), 7.25 (2H, d, J=8.8 Hz),7.31 (2H, d, J=8.6 Hz), 7.55-7.61 (1H, m), 7.64 (1H, dd, J=2.0, 7.2 Hz),7.77 (1H, s).

Example 141

[1211] Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[1212] Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted toyield the title compound as a pale brown crystalline powder (yield:84.7%).

[1213] Melting point: 186.7-197.0° C. (dec.)

[1214]¹H NMR (400 MHz, DMSO-d₆) δ: 2.31 (3H, d, J=2.0 Hz), 3.15 (4H,br), 3.31 (4H, t, J=5.2 Hz), 3.94 (2H, s), 4.95 (2H, dd, J=1.3, 6.3 Hz),6.47 (1H, dt, J=15.9, 6.1 Hz), 6.66 (1H, d, J=15.9 Hz), 7.22 (1H, dd,J=9.0, 9.0 Hz), 7.34 (2H, d, J=8.6 Hz), 7.45 (2H, d, J=8.6 Hz),7.73-7.78 (1H, m), 7.82 (1H, dd, J=1.9, 7.6 Hz), 8.21 (1H, s).

[1215] IR (KBr) cm⁻¹: 1656, 1606, 1240, 1090, 964.

[1216] Mass m/z: 452 (M⁺), 454 (M⁺)

Example 142

[1217] Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1218] Following the procedure of Example 1 (10),2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 71.8%).

[1219]¹H NMR (400 MHz, CDCl₃) δ: 2.32 (3H, s), 2.35 (3H, s), 2.51 (4H,br), 2.62 (4H, br), 3.59 (2H, s), 4.99 (2H, d, J=6.6 Hz), 6.42 (1H, dt,J=15.8, 6.4 Hz), 6.66 (1H, d, J=15.9 Hz), 7.09 (1H, dd, J=8.9, 8.9 Hz),7.24 (2H, d, J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz), 7.56-7.62 (1H, m), 7.65(1H, dd, J=1.8, 7.2 Hz), 7.76 (1H, s).

Example 143

[1220] Preparation of2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[1221] Following the procedure of Example 4,2-(4-chloro-cinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield thetitle compound as a colorless crystalline powder (yield: 80.4%).

[1222] Melting point: 229.7-243.3° C. (dec.)

[1223]¹H NMR (400 MHz, DMSO-d₆) δ: 2.31 (3H, d, J=1.8 Hz), 2.76 (3H, s),3.09 (4H, br), 3.33 (4H, br), 3.83 (2H, s), 4.94 (2H, dd, J=1.2, 6.0Hz), 6.42 (1H, dt, J=16.0, 6.2 Hz), 6.65 (1H, d, J=16.0 Hz), 7.22 (1H,dd, J=9.1, 9.1 Hz), 7.34 (2H, d, J=8.6 Hz), 7.45 (2H, d, J=8.6 Hz),7.71-7.76 (1H, m), 7.80 (1H, dd, J=2.2, 7.0 Hz), 8.08 (1H, s).

[1224] IR (KBr) cm⁻¹: 1652, 1608, 1492, 1239, 1130.

[1225] Mass m/z: 466 (M⁺), 468 (M⁺).

Example 144

[1226] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1227] Following the procedure of Example 1 (10),2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 76.6%).

[1228]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, s), 2.70 (4H, t, J=4.5 Hz),3.66 (4H, t, J=4.9 Hz), 3.70 (2H, s), 4.98 (2H, d, J=6.6 Hz), 6.36 (1H,dt, J=15.8, 6.5 Hz), 6.63 (1H, d, J=15.8 Hz), 7.06 (1H, dd, J=8.6, 8.6Hz), 7.24 (2H, d, J=8.6 Hz), 7.30 (2H, d, J=8.2 Hz), 7.58-7.63 (1H, m),7.65 (1H, dd, J=1.8, 7.2 Hz), 7.78 (1H, s).

Example 145

[1229] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one hydrochloride

[1230] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 76.1%).

[1231] Melting point: 151.9-153.4° C.

[1232]¹H NMR (400 MHz, DMSO-d₆) δ: 2.32 (3H, d, J=1.7 Hz), 3.35 (4H, t,J=5.1 Hz), 3.83 (4H, t, J=5.4 Hz), 4.46 (2H, s), 4.97 (2H, dd, J=1.2,6.1 Hz), 6.48 (1H, dt, J=15.9, 6.2 Hz), 6.67 (1H, d, J=15.9 Hz), 7.24(1H, dd, J=9.1, 9.1 Hz), 7.35 (2H, d, J=8.8 Hz), 7.45 (2H, d, J=8.6 Hz),7.75-7.80 (1H, m), 7.85 (1H, dd, J=1.7, 7.9 Hz), 8.48 (1H, s).

[1233] IR (KBr) cm⁻¹: 1652, 1604, 1492, 1240, 1090, 968.

[1234] Mass m/z: 440 (M⁺), 442 (M⁺)

Example 146

[1235] Preparation of2-(4-chlorocinnamyl)-4-dimethylamino-methyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1236] Following the procedure of Example 7,2-(4-chloro-cinnamyl)-6-(4-fluoro-3-methylphenyl)-4-methane-sulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 84.6%).

[1237]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, d, J=1.6 Hz), 2.36 (6H, s),3.52 (2H, d, J=1.2 Hz), 4.99 (2H, dd, J=1.0, 6.6 Hz), 6.43 (1H, dt,J=15.8, 6.6 Hz), 6.66 (1H, d, J=15.8 Hz), 7.07 (1H, dd, J=8.9, 8.9 Hz),7.24 (2H, d, J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz), 7.60-7.68 (2H, m), 7.77(1H, s).

Example 147

[1238] Preparation of2-(4-chlorocinnamyl)-4-dimethylamino-methyl-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one hydrochloride

[1239] Following the procedure of Example 4,2-(4-chloro-cinnamyl)-4-dimethylaminomethyl-6-(4-fluoro-3-methyl-phenyl)-2H-pyridazin-3-one was reacted to yield the title compoundas a colorless crystalline powder (yield: 34.4%).

[1240] Melting point: 201.3-201.9° C.

[1241]¹H NMR (400 MHz, DMSO-d₆) δ: 2.32 (3H, d, J=1.7 Hz), 2.83 (6H, s),4.28 (2H, s), 4.98 (2H, dd, J=1.3, 6.1 Hz), 6.48 (1H, dt, J=16.1, 6.1Hz), 6.67 (1H, d, J=16.1 Hz), 7.24 (1H, dd, J=9.3, 9.3 Hz), 7.35 (2H, d,J=8.6 Hz), 7.45 (2H, d, J=8.6 Hz), 7.75-7.80 (1H, m), 7.85 (1H, dd,J=2.3, 7.6 Hz), 8.47 (1H, s).

[1242] IR (KBr) cm⁻¹: 1652, 1608, 1491, 1239, 968.

[1243] Mass m/z: 411 (M⁺), 413 (M⁺).

Example 148

[1244] Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1245] 1) Preparation of4-carboxy-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1246] Following the procedure of Example 1 (7),2-cyclopropylmethyl-4-methoxycarbonyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as ayellow crystalline powder (yield: 98.2%).

[1247]¹H NMR (400 MHz, CDCl₃) δ: 0.50-0.66 (4H, m), 1.40-1.53 (1H, m),2.54 (3H, s), 4.24 (2H, d, J=7.4 Hz), 7.34 (2H, d, J=8.6 Hz), 7.78 (2H,d, J=8.6 Hz), 8.66 (1H, s), 14.22 (1H, s).

[1248] IR (KBr) cm⁻¹: 3430, 1752, 1631, 1472, 1452, 1403, 1093, 825.

[1249] Mass m/z: 316 (M⁺)

[1250] 2) Preparation of2-cyclopropylmethyl-4-hydroxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1251] Following the procedure of Example 1 (8),4-carboxy-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as a pale yellowcrystalline powder (yield: 22.6%).

[1252]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.60 (4H, m), 1.37-1.46 (1H, m),2.53 (3H, s), 3.09 (1H, t, J=6.1 Hz), 4.11 (2H, d, J=7.2 Hz), 4.72 (2H,d, J=6.0 Hz), 7.32 (2H, d, J=8.6 Hz), 7.67 (1H, s), 7.74 (2H, d, J=8.6Hz).

[1253] IR (KBr) cm⁻¹: 3393, 1657, 1602, 1514, 1095, 822.

[1254] Mass m/z: 302 (M⁺).

[1255] 3) Preparation of2-cyclopropylmethyl-4-methanesulfonyloxy-methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1256] Following the procedure of Example 1 (9),2-cyclopropylmethyl-4-hydroxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow fine-needles(yield: 78.6%).

[1257]¹H NMR (400 MHz, CDCl₃) δ: 0.45-1.61 (4H, m), 1.37-1.47 (1H, m),2.53 (3H, s), 3.17 (3H, s), 4.11 (2H, d, J=7.2 Hz), 5.28 (2H, s), 7.33(2H, d, J=8.4 Hz), 7.74 (2H, d, J=8.4 Hz), 7.79 (1H, s).

[1258] IR (KBr) cm⁻¹: 3446, 1652, 1607, 1359, 1178, 1024, 829.

[1259] Mass m/z: 380 (M⁺).

[1260] 4) Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1261] Following the procedure of Example 1 (10),2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methyl-piperazine were reacted toyield the title compound as a yellow oil (yield: 85.7%).

[1262]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.58 (4H, m), 1.36-1.48 (1H, m),2.33 (3H, s), 2.53 (3H, s), 2.47-2.66 (8H, m), 3.59 (2H, s), 4.10 (2H,d, J=7.3 Hz), 7.33 (2H, d, J=8.3 Hz), 7.75 (2H, d, J=8.3 Hz), 7.78 (1H,s).

Example 149

[1263] Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onedihydrochloride

[1264] Following the procedure of Example 4,2-cyclopropyl-methyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 69.1%).

[1265] Melting point: 234.6-239.2° C.

[1266]¹H NMR (400 MHz, DMSO-d₆) δ: 0.40-0.45 (2H, m), 0.50-0.56 (2H, m),1.30-1.40 (1H, m), 2.53 (3H, s), 2.77 (3H, s), 2.97 (4H, br), 3.28 (4H,br), 3.72 (2H, s), 4.05 (2H, d, J=7.1 Hz), 7.39 (2H, d, J=8.6 Hz), 7.82(2H, d, J=8.3 Hz), 7.96 (1H, s).

[1267] IR (KBr) cm⁻¹: 3438, 1651, 1606, 1402, 1095.

[1268] Mass m/z: 384 (M⁺).

Example 150

[1269] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1270] Following the procedure of Example 1 (10),2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and diethanolamine were reacted to yieldthe title compound as a yellow oil (yield: 78.9%).

[1271]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.59 (4H, m), 1.36-1.45 (1H, m),2.53 (3H, s), 2.73 (4H, br), 3.67 (4H, t, J=4.9 Hz), 3.73 (2H, s), 4.13(2H, d, J=7.3 Hz), 7.32 (2H, d, J=8.3 Hz), 7.70 (1H, s), 7.74 (2H, d,J=8.3 Hz).

Example 151

[1272] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one hydrochloride

[1273] Following the procedure of Example 4,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly yellow solid(yield: 75.1%).

[1274] Melting point: 169.2-171.7° C.

[1275]¹H NMR (400 MHz, DMSO-d₆) δ: 0.42-0.46 (2H, m), 0.52-0.57 (2H, m),1.30-1.40 (1H, m), 2.53 (3H, s), 3.31 (4H, br), 3.81 (4H, t, J=5.3 Hz),4.42 (2H, s), 7.41 (2H, d, J=8.8 Hz), 7.85 (2H, d, J=9.0 Hz), 8.37 (1H,s).

[1276] IR (KBr) cm⁻¹: 3242, 1652, 1604, 1420, 1094, 1059, 823.

[1277] Mass m/z: 358 (M⁺-CH₂OH).

Example 152

[1278] Preparation of2-cyclopropylmethyl-4-dimethylamino-methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1279] Following the procedure of Example 7,2-cyclopropyl-methyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one was reacted to yield the title compoundas a yellow oil (yield: 98.6%).

[1280]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.58 (4H, m), 1.36-1.48 (1H, m),2.35 (6H, s), 3.51 (2H, s), 4.51 (2H, d, J=7.3 Hz), 7.31 (2H, d, J=8.3Hz), 7.77 (2H, d, J=7.8 Hz), 7.78 (1H, s).

Example 153

[1281] Preparation of2-cyclopropylmethyl-4-dimethylamino-methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one hydrochloride

[1282] Following the procedure of Example 4,2-cyclopropyl-methyl-4-dimethylaminomethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 75.5%).

[1283] Melting point: 230.2-232.3° C.

[1284]¹H NMR (400 MHz, DMSO-d₆) δ: 0.42-0.46 (2H, m), 0.52-0.58 (2H, m),1.31-1.40 (1H, m), 2.53 (3H, s), 2.82 (6H, s), 4.09 (2H, d, J=7.1 Hz),4.25 (2H, s), 7.41 (2H, d, J=8.6 Hz), 7.84 (2H, d, J=8.5 Hz), 8.34 (1H,s).

[1285] IR (KBr) cm⁻¹: 3435, 1646, 1604, 1402, 1093, 829.

[1286] Mass m/z: 329 (M⁺).

Example 154

[1287] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one

[1288] 1) Preparation of4-carboxy-2-isobutyl-6-[4-(methylthio)-phenyl]-2H-pyrid azin-3-one

[1289] To a solution of4-methoxycarbonyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one (8.00 g,29.0 mmol) in N,N-dimethylformamide (80 mL) were added potassiumcarbonate (8.02 g, 58.0 mmol) and isobutyl bromide (4.76 g, 34.8 mmol),and the mixture was stirred at 80° C. for 2 hours. The temperature ofthe reaction mixture was allowed to drop back to room temperature, and asaturated aqueous solution of sodium hydrogencarbonate was added. Themixture was then extracted with ethyl acetate. The extract was washedwith brine, and dried over anhydrous sodium sulfate. The solvent wasdistilled off. Following the procedure of the residue was reacted toyield the title compound as a yellow solid [yield: 65.1% (2 steps)].

[1290]¹H NMR (400 MHz, CDCl₃) δ: 1.01 (6H, d, J=6.6 Hz), 2.33-2.46 (1H,m), 2.54 (3H, s), 4.21 (2H, d, J=7.4 Hz), 7.34 (2H, d, J=8.4 Hz), 7.80(2H, d, J=8.4 Hz), 8.68 (1H, s), 12.72 (1H, s).

[1291] Mass m/z: 318 (M⁺).

[1292] 2) Preparation of4-hydroxymethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1293] Following the procedure of Example 1 (8),4-carboxy-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one wasreacted to yield the title compound as a yellow oil (yield: 35.3%).

[1294]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.27-2.39 (1H,m), 2.53 (3H, s), 4.08 (2H, d, J=7.4 Hz), 4.71 (2H, d, J=5.9 Hz), 7.26(2H, d, J=8.4 Hz), 7.66 (1H, s), 7.73 (2H, d, J=8.6 Hz).

[1295] 3) Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1296] Following the procedure of Example 1 (9),4-hydroxymethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyri dazin-3-onewas reacted to yield the title compound as a pale yellow crystallinepowder (yield: 73.2%).

[1297]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.28-2.40 (1H,m), 2.53 (3H, s), 3.17 (3H, s), 4.08 (2H, d, J=7.4 Hz), 5.27 (2H, d,J=1.2 Hz), 7.32 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 7.75 (1H, d,J=1.4 Hz).

[1298] Mass m/z: 382 (M⁺).

[1299] 4) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1300] Following the procedure of Example 1 (10),2-isobutyl-6-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate werereacted to yield the title compound as a yellow oil (yield: 88.0%).

[1301]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 1.47 (9H, s),2.28-2.40 (1H, m), 2.50-2.55 (4H, m), 2.53 (3H, s), 3.50 (4H, t, J=4.8Hz), 3.58 (2H, s), 4.07 (2H, d, J=7.4 Hz), 7.32 (2H, d, J=8.4 Hz), 7.73(2H, d, J=8.6 Hz), 7.78 (1H, s).

Example 155

[1302] Preparation of2-isobutyl-6-[4-(methylthio)phenyl]-4-(1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[1303] Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow crystalline powder(yield: 70.5%).

[1304] Melting point: 248.5-253.7° C.(dec.)

[1305]¹H NMR (400 MHz, DMSO-d₆) δ: 0.95 (6H, d, J=6.6 Hz), 2.21-2.33(1H, m), 2.52 (3H, s), 3.10 (4H, t, J=4.8 Hz), 3.30 (4H, t, J=5.2 Hz),3.90 (2H, s), 4.01 (2H, d, J=7.3 Hz), 7.39 (2H, d, J=8.3 Hz), 7.83 (2H,d, J=8.3 Hz), 8.15 (1H, s).

[1306] IR (KBr) cm⁻¹: 2961, 2442, 1640, 1596, 1511, 1433, 1406, 1089,912.

[1307] Mass m/z: 372 (M⁺)

Example 156

[1308] Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1309] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield thetitle compound as a yellow oil (yield: 68.3%).

[1310]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.29-2.39 (1H,m), 2.32 (3H, s), 2.51 (4H, br), 2.53 (3H, s), 2.62 (4H, br), 3.58 (2H,d, J=1.4 Hz), 4.07 (2H, d, J=7.4 Hz), 7.33 (2H, d, J=8.6 Hz), 7.74 (2H,d, J=6.8 Hz), 7.76 (1H, s).

Example 157

[1311] Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one dihydrochloride

[1312] Following the procedure of Example 4,2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one was reacted to yield the title compound asa colorless crystalline powder (yield: 86.4%).

[1313] Melting point: 242.6-243.7° C.

[1314]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.21-2.33(1H, m), 2.52 (3H, s), 2.76 (3H, s), 3.09 (4H, br), 3.33 (4H, br), 3.83(2H, s), 4.01 (2H, d, J=7.1 Hz), 7.39 (2H, d, J=8.6 Hz), 7.82 (2H, d,J=8.5 Hz), 8.07 (1H, s).

[1315] IR (KBr) cm⁻¹: 3432, 2957, 2437, 1652, 1607, 1090, 953.

[1316] Mass m/z: 386 (M⁺).

Example 158

[1317] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1318] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and diethanolamine were reacted to yield thetitle compound as a yellow oil (yield: 71.2%).

[1319]¹H NMR (400 MHz, CDCl₃) δ: 0.96 (6H, d, J=6.6 Hz), 2.27-2.39 (1H,m), 2.51 (3H, s), 2.71 (4H, t, J=5.1 Hz), 3.66 (4H, t, J=5.1 Hz), 3.70(2H, s), 4.08 (2H, d, J=7.2 Hz), 7.30 (2H, d, J=8.6 Hz), 7.71-7.76 (3H,m).

Example 159

[1320] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-oneoxalate

[1321] To a solution of4-N,N-bis(2-hydroxyethyl)amino-methyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (69.7 mg, 0.18 mmol) in methanol (1mL) was added at room temperature oxalic acid dihydrate (22.4 mg, 0.18mmol). The solvent was distilled off. The residue was recrystallizedfrom chloroform-diethyl ether to obtain the title compound as a whitesolid (59.5 mg, 69.4%).

[1322] Melting point: 116.4-118.1° C.

[1323]¹H NMR (400 MHz, DMSO-d₆) δ: 0.94 (6H, d, J=6.6 Hz), 2.20-2.33(1H, m), 2.52 (3H, s), 2.91 (4H, t, J=5.8 Hz), 3.61 (4H, t, J=5.6 Hz),3.94 (2H, s), 4.01 (2H, d, J=7.3 Hz), 7.39 (2H, d, J=8.6 Hz), 7.81 (2H,d, J=8.6 Hz), 8.14 (1H, s).

[1324] IR (KBr) cm⁻¹: 3344, 2927, 1659, 1611, 1402, 1049, 721.

[1325] Mass m/z: 360 (M⁺-CH₂OH)

Example 160

[1326] Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one

[1327] Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as ayellow oil (yield: 73.9%).

[1328]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.29-2.41 (1H,m), 2.36 (6H, s), 2.52 (3H, s), 3.52 (2H, d, J=1.2 Hz), 4.07 (2H, d,J=7.4 Hz), 7.31 (2H, d, J=8.6 Hz), 7.77 (2H, d, J=8.4 Hz), 7.79 (1H, s).

Example 161

[1329] Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one hydrochloride

[1330] Following the procedure of Example 4,4-dimethyl-aminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 82.3%).

[1331] Melting point: 216.8-218.4° C.

[1332]¹H NMR (400 MHz, DMSO-d₆) δ: 0.96 (6H, d, J=6.8 Hz), 2.23-2.36(1H, m), 2.53 (3H, s), 2.82 (6H, s), 4.05 (2H, d, J=7.1 Hz), 4.27 (2H,s), 7.41 (2H, d, J=8.3 Hz), 7.84 (2H, d, J=8.3 Hz), 8.42 (1H, s).

[1333] IR (KBr) cm⁻¹: 3485, 1740, 1684, 1253, 856, 577.

[1334] Mass m/z: 331 (M⁺).

Example 162

[1335] Preparation of2-isobutyl-6-[4-(methylthio)phenyl]-4-propargylaminomethyl-2H-pyridazin-3-one

[1336] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and propargylamine were reacted to yield thetitle compound as a yellow oil (yield: 52.2%).

[1337]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.26 (1H, t,J=2.3 Hz), 2.29-2.40 (1H, m), 2.52 (3H, s), 3.51 (2H, d, J=2.4 Hz), 3.90(2H, s), 4.07 (2H, d, J=7.4 Hz), 7.31 (2H, d, J=8.4 Hz), 7.70 (1H, s),7.73 (2H, d, J=8.4 Hz).

Example 163

[1338] Preparation of2-isobutyl-6-[4-(methylthio)phenyl]-4-propargylaminomethyl-2H-pyridazin-3-one hydrochloride

[1339] Following the procedure of Example 4,2-isobutyl-6-[4-(methylthio)phenyl]-4-propargylaminomethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a white solid (yield: 73.6%).

[1340] Melting point: 197.5-198.4° C.

[1341]¹H NMR (400 MHz, DMSO-d₆) δ: 0.96 (6H, d, J=6.6 Hz), 2.23-2.36(1H, m), 2.53 (3H, s), 3.48 (1H, t, J=2.4 Hz), 3.95 (2H, d, J=2.4 Hz),4.03 (2H, d, J=7.1 Hz), 4.17 (2H, s), 7.41 (2H, d, J=8.3 Hz), 7.82 (2H,d, J=8.6 Hz), 8.28 (1H, s).

[1342] IR (KBr) cm⁻¹: 3447, 3207, 2958, 2122, 1651, 1607, 1441, 1093.

[1343] Mass m/z: 341 (M⁺).

Example 164

[1344] Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

[1345] 1) Preparation of2-cyclopropylmethyl-4-methanesulfonyloxy-methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

[1346] To a solution of2-cyclopropylmethyl-4-methane-sulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (300 mg, 0.79 mmol) in methylenechloride (10 mL) was added dropwise at −20° C. a solution of3-chloroperbenzoic acid (204 mg, 1.12 mmol) in methylene chloride (2mL), and at the same temperature, the mixture was stirred for 30minutes. A 10% aqueous sodium hydrogensulfite was added to the reactionmixture, and then, the mixture was extracted with chloroform. Theextract was successively washed with a saturated aqueous sodiumhydrogencarbonate and brine, and was then dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was recrystallized from chloroform-hexane to yield the titlecompound as a colorless crystalline powder (139 mg, 44.5%).

[1347]¹H NMR (400 MHz, CDCl₃) δ: 0.48-0.63 (4H, m), 1.37-1.46 (1H, m),2.77 (3H, s), 3.18 (3H, s), 4.14 (2H, d, J=7.3 Hz), 5.30 (2H, d, J=1.4Hz), 7.76 (2H, d, J=8.6 Hz), 7.84 (1H, t, J=1.4 Hz), 7.98 (2H, d, J=8.8Hz).

[1348] Mass m/z: 396 (M⁺)

[1349] 2) Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

[1350] Following the procedure of Example 1 (10),2-cyclopropyl-4-methanesulfonyloxymethyl-6-[4-(methyl-sulfinyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted toyield the title compound as a yellow oil (yield: 60.6%).

[1351]¹H NMR (400 MHz, CDCl₃) δ: 0.46-0.60 (4H, m), 1.37-1.49 (1H, m),2.34 (3H, s), 2.54 (4H, br), 2.64 (4H, br), 2.78 (3H, s), 3.61 (2H, s),4.13 (2H, d, J=7.2 Hz), 7.75 (2H, d, J=8.2 Hz), 7.84 (1H, s), 7.99 (2H,d, J=8.2 Hz).

Example 165

[1352] Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-onedihydrochloride

[1353] Following the procedure of Example 4,2-cyclopropyl-methyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methyl-sulfinyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 64.3%).

[1354] Melting point: 80° C. (dec.)

[1355]¹H NMR (400 MHz, DMSO-d₆) δ: 0.41-0.57 (4H, m), 1.30-1.41 (1H, m),2.76 (3H, s), 2.77 (3H, s), 3.01 (4H, br), 3.31 (4H, br), 3.77 (2H, s),4.08 (2H, d, J=6.8 Hz), 7.80 (2H, d, J=8.3 Hz), 8.05-8.09 (3H, m).

[1356] IR (KBr) cm⁻¹: 3430, 3005, 1652, 1607, 1458, 1401, 1010, 838.

[1357] Mass m/z: 400 (M⁺)

Example 166

[1358] Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

[1359] 1) Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

[1360] Following the procedure of Example 164 (1),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as acolorless crystalline powder (yield: 54.3%).

[1361]¹H NMR (400 MHz, CDCl₃) δ: 1.00 (6H, d, J=6.8 Hz), 2.29-2.41 (1H,m), 2.77 (3H, s), 3.18 (3H, s), 4.11 (2H, d, J=7.3 Hz), 5.29 (2H, d,J=1.5 Hz), 7.76 (2H, d, J=8.8 Hz), 7.83 (1H, t, J=1.2 Hz), 7.98 (2H, d,J=8.6 Hz).

[1362] Mass m/z: 398 (M⁺)

[1363] 2) Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

[1364] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yieldthe title compound as a yellow oil (yield: 61.8%).

[1365]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.30-2.41 (1H,m), 2.34 (3H, s), 2.54 (4H, br), 2.64 (4H, br), 2.77 (3H, s), 3.60 (2H,s), 4.10 (2H, d, J=7.4 Hz), 7.75 (2H, d, J=8.2 Hz), 7.82 (1H, s), 7.99(2H, d, J=8.2 Hz)

Example 167

[1366] Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one dihydrochloride

[1367] Following the procedure of Example 4,2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfinyl)-phenyl]-2H-pyridazin-3-one was reacted to yield the titlecompound as a colorless crystalline powder (yield: 76.1%).

[1368] Melting point: 224.5-229.1° C. (dec.)

[1369]¹H NMR (400 MHz, DMSO-d₆) δ: 0.96 (6H, d, J=6.6 Hz), 2.22-2.35(1H, m), 2.76 (3H, s), 2.77 (3H, s), 3.14 (4H, br), 3.35 (4H, br), 3.87(2H, s), 4.04 (2H, d, J=7.1 Hz), 7.80 (2H, d, J=8.3 Hz), 8.07 (2H, d,J=8.3 Hz), 8.18 (1H, s).

[1370] IR (KBr) cm⁻¹: 3426, 2960, 1656, 1608, 1459, 1400, 1044, 1011.

[1371] Mass m/z: 402 (M⁺).

Example 168

[1372] Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one

[1373] Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as ayellow oil (yield: 46.2%).

[1374]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.30-2.43 (1H,m), 2.38 (6H, s), 2.76 (3H, s), 3.54 (2H, s), 4.10 (2H, d, J=7.4 Hz),7.74 (2H, d, J=8.2 Hz), 7.87 (1H, s), 8.02 (2H, d, J=8.2 Hz).

Example 169

[1375] Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfinyl)phenyl]-2H-pyridazin-3-onehydrochloride

[1376] Following the procedure of Example 4,4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfinyl)-phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as acolorless crystalline powder (yield: 77.4%).

[1377] Melting point: 204.2-206.0° C.

[1378]¹H NMR (400 MHz, DMSO-d₆) δ: 0.97 (6H, d, J=6.6 Hz), 2.24-2.36(1H, m), 2.78 (3H, s), 2.83 (6H, s), 4.07 (2H, d, J=7.1 Hz), 4.28 (2H,s), 7.82 (2H, d, J=8.3 Hz), 8.09 (2H, d, J=8.3 Hz), 8.49 (1H, s).

[1379] IR (KBr) cm⁻¹: 3438, 2961, 1652, 1607, 1467, 1400, 1047.

[1380] Mass m/z: 347 (M⁺).

Example 170

[1381] Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

[1382] 1) Preparation of2-cyclopropylmethyl-4-methanesulfonyloxy-methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

[1383] To a solution of2-cyclopropylmethyl-4-methane-sulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (226 mg, 0.59 mmol) in methylenechloride (10 mL) was added dropwise at −20° C. a solution of3-chloroperbenzoic acid (410 mg, 2.38 mmol) in methylene chloride (2mL), and at the same temperature, the mixture was stirred for 30minutes. A 10% aqueous sodium hydrogensulfite was added to the reactionmixture, and then, the mixture was extracted with chloroform. Theextract was successively washed with a saturated aqueous sodiumhydrogencarbonate and brine, and was then dried over anhydrous sodiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was recrystallized from chloroform-hexane to yield the titlecompound as a colorless crystalline powder (209 mg, 85.3%).

[1384]¹H NMR (400 MHz, CDCl₃) δ: 0.46-0.63 (4H, m), 1.37-1.46 (1H, m),3.10 (3H, s), 3.18 (3H, s), 4.20 (2H, d, J=7.3 Hz), 5.31 (2H, d, J=1.2Hz), 7.86 (1H, t, J=1.2 Hz), 8.02 (2H, d, J=8.8 Hz), 8.06 (2H, d, J=9.0Hz).

[1385] Mass m/z: 412 (M⁺).

[1386] 2) Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

[1387] Following the procedure of Example 1 (10),2-cyclopropyl-4-methanesulfonyloxymethyl-6-[4-(methyl-sulfonyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted toyield the title compound as a yellow oil (yield: 80.9%).

[1388]¹H NMR (400 MHz, CDCl₃) δ: 0.46-0.61 (4H, m), 1.38-1.48 (1H, m),2.34 (3H, s), 2.54 (4H, br), 2.64 (4H, br), 3.10 (3H, s), 3.61 (2H, d,J=1.2 Hz), 4.13 (2H, d, J=7.1 Hz), 7.85 (1H, t, J=1.2 Hz), 8.03 (2H, d,J=9.0 Hz), 8.05 (2H, d, J=9.0 Hz).

Example 171

[1389] Preparation of2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onedihydrochloride

[1390] Following the procedure of Example 4,2-cyclopropyl-methyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methyl-sulfonyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 76.8%).

[1391] Melting point: 209.0-211.4° C.

[1392]¹H NMR (400 MHz, DMSO-d₆) δ: 0.41-0.46 (2H, m), 0.52-0.57 (2H, m),1.31-1.41 (1H, m), 2.77 (3H, s), 3.04 (4H, br), 3.21 (3H, s), 3.31 (4H,br), 3.80 (2H, s), 4.09 (2H, d, J=7.1 Hz), 8.04 (2H, d, J=8.3 Hz), 8.12(1H, s), 8.14 (2H, d, J=8.3 Hz).

[1393] IR (KBr) cm⁻¹: 3434, 3012, 1652, 1596, 1458, 1402, 1302, 1150.

[1394] Mass m/z: 416 (M⁺).

Example 172

[1395] Preparation of2-cyclopropylmethyl-4-dimethylamino-methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

[1396] Following the procedure of Example 1 (10),2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a yellowoil (yield: 65.6%).

[1397]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.62 (4H, m), 1.39-1.49 (1H, m),2.38 (6H, s), 3.09 (3H, s), 3.55 (2H, s), 4.14 (2H, d, J=7.2 Hz), 7.89(1H, s), 8.02 (2H, d, J=8.4 Hz), 8.06 (2H, d, J=8.6 Hz).

Example 173

[1398] Preparation of2-cyclopropylmethyl-4-dimethylamino-methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one hydrochloride

[1399] Following the procedure of Example 4,2-cyclopropyl-methyl-4-dimethylaminomethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one was reacted to yield the title compoundas a colorless crystalline powder (yield: 63.4%).

[1400] Melting point: 239.5-240.7° C.

[1401]¹H NMR (400 MHz, DMSO-d₆) δ: 0.43-0.59 (4H, m), 1.33-1.43 (1H, m),2.83 (6H, s), 3.23 (3H, s), 4.13 (2H, d, J=7.1 Hz), 4.29 (2H, s), 8.06(2H, d, J=7.8 Hz), 8.17 (2H, d, J=8.3 Hz), 8.57 (1H, s).

[1402] IR (KBr) cm⁻¹: 3447, 2674, 1646, 1608, 1596, 1306, 1150, 777.

[1403] Mass m/z: 361 (M⁺).

Example 174

[1404] Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-[4-(methyl-sulfonyl)phenyl]-2H-pyridazin-3-one

[1405] 1) Preparation of2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

[1406] Following the procedure of Example 170 (1),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as acolorless crystalline powder (yield: 97.8%).

[1407]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.29-2.41 (1H,m), 3.10 (3H, s), 3.18 (3H, s), 4.12 (2H, d, J=7.3 Hz), 5.29 (2H, d,J=1.2 Hz), 7.85 (1H, t, J=1.4 Hz), 8.02 (2H, d, J=8.8 Hz), 8.05 (2H, d,J=8.8 Hz)

[1408] Mass m/z: 414 (M⁺)

[1409] 2) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)-methyl-2-isobutyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

[1410] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and tert-butyl 1-piperazinecarboxylate werereacted to yield the title compound as a yellow oil (yield: 75.9%).

[1411]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 1.47 (9H, s),2.29-2.41 (1H, m), 2.54 (4H, br), 3.09 (3H, s), 3.51 (4H, br), 3.60 (2H,s), 4.11 (2H, d, J=7.2 Hz), 7.86 (1H, s), 8.02 (2H, d, J=8.8 Hz), 8.05(2H, d, J=8.8 Hz).

Example 175

[1412] Preparation of2-isobutyl-6-[4-(methylsulfonyl)-phenyl]-4-(1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[1413] Following the procedure of Example 2,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-isobutyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 88.2%).

[1414] Melting point: 222.4-224.2° C.

[1415]¹H NMR (400 MHz, DMSO-d₆) δ: 0.96 (6H, d, J=6.8 Hz), 2.22-2.35(1H, m), 3.06 (4H, br), 3.21 (3H, s), 3.28 (4H, t, J=5.2 Hz), 3.87 (2H,s), 4.05 (2H, d, J=7.1 Hz), 8.04 (2H, d, J=8.6 Hz), 8.14 (2H, d, J=8.3Hz) 8.22 (1H, s).

[1416] IR (KBr) cm⁻¹: 3421, 2957, 1656, 1611, 1597, 1305, 1149, 961.

[1417] Mass m/z: 404 (M⁺).

Example 176

[1418] Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

[1419] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yieldthe title compound as a yellow oil (yield: 88.5%).

[1420]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.8 Hz), 2.28-2.40 (1H,m), 2.37 (3H, s), 2.53 (4H, br), 2.63 (4H, br), 3.10 (3H, s), 3.60 (2H,s), 4.10 (2H, d, J=7.3 Hz), 7.84 (1H, s), 8.02 (2H, d, J=9.0 Hz), 8.05(2H, d, J=8.8 Hz)

Example 177

[1421] Preparation of2-isobutyl-4-(4-methyl-1-piperazinyl)-methyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one dihydrochloride

[1422] Following the procedure of Example 4,2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylsulfonyl)-phenyl]-2H-pyridazin-3-one was reacted to yield the titlecompound as a colorless crystalline powder (yield: 62.0%).

[1423] Melting point: 224.5-228.0° C.

[1424]¹H NMR (400 MHz, DMSO-d₆) δ: 0.95 (6H, d, J=6.8 Hz), 2.23-2.35(1H, m), 2.76 (3H, s), 3.08 (4H, br), 3.21 (3H, s), 3.32 (4H, br), 3.83(2H, s), 4.05 (2H, d, J=7.1 Hz), 8.04 (2H, d, J=8.3 Hz), 8.13 (2H, d,J=8.5 Hz), 8.15 (1H, s).

[1425] IR (KBr) cm⁻¹: 3447, 2958, 1652, 1610, 1596, 1319, 1152, 955.

[1426] Mass m/z: 418 (M⁺)

Example 178

[1427] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-isobutyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

[1428] Following the procedure of Example 1 (10),2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one and diethanolamine were reacted to yield thetitle compound as a yellow oil (yield: 51.1%).

[1429]¹H NMR (400 MHz, CDCl₃) δ: 0.98 (6H, d, J=6.6 Hz), 2.28-2.40 (1H,m), 2.73 (4H, t, J=4.8 Hz), 3.08 (3H, s), 3.68 (4H, t, J=4.9 Hz), 3.73(2H, s), 4.11 (2H, d, J=7.4 Hz), 7.93 (1H, s), 8.00 (2H, d, J=8.6 Hz),8.05 (2H, d, J=8.8 Hz).

[1430] Mass m/z: 392 (M⁺-CH₂OH).

Example 179

[1431] Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one

[1432] Following the procedure of Example 7,2-isobutyl-4-methanesulfonyloxymethyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as ayellow oil (yield: 82.1%).

[1433]¹H NMR (400 MHz, CDCl₃) δ: 0.99 (6H, d, J=6.6 Hz), 2.30-2.41 (1H,m), 2.37 (6H, s), 3.09 (3H, s), 3.52 (2H, s), 4.11 (2H, d, J=7.2 Hz),7.86 (1H, s), 8.02 (2H, d, J=8.8 Hz), 8.05 (2H, d, J=8.8 Hz).

Example 180

[1434] Preparation of4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfonyl)phenyl]-2H-pyridazin-3-onehydrochloride

[1435] Following the procedure of Example 4,4-dimethylaminomethyl-2-isobutyl-6-[4-(methylsulfonyl)-phenyl]-2H-pyridazin-3-one was reacted to yield the title compound as acolorless crystalline powder (yield: 58.6%).

[1436] Melting point: 221.4-223.3° C.

[1437]¹H NMR (400 MHz, DMSO-d₆) δ: 0.97 (6H, d, J=6.6 Hz), 2.25-2.36(1H, m), 2.82 (6H, s), 3.22 (3H, s), 4.08 (2H, d, J=7.3 Hz), 4.28 (2H,s), 8.06 (2H, d, J=8.3 Hz), 8.15 (2H, d, J=8.5 Hz), 8.55 (1H, s).

[1438] IR (KBr) cm⁻¹: 3447, 2963, 1653, 1609, 1597, 1307, 1152, 777.

[1439] Mass m/z: 363 (M⁺).

Example 181

[1440] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-pyrrolidinomethyl-2H-pyridazin-3-one

[1441] Following the procedure of Example 1 (10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and pyrrolidine were reacted toyield the title compound as a yellow oil (yield: 75.9%).

[1442]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.61 (4H, m), 1.42 (1H, m),1.85-2.00 (4H, m), 2.70-3.00 (4H, m), 3.83 (2H, brs), 3.94 (3H, s), 4.10(2H, d, J=7.3 Hz), 7.03 (1H, dd, J=8.5, 8.5 Hz), 7.60 (1H, d, J=8.5 Hz),7.65 (1H, dd, J=8.5, 2.0 Hz), 8.00 (1H, brs).

[1443] IR (Neat) cm⁻¹: 1652, 1608, 1523, 1438, 1286, 758.

[1444] Mass m/z: 357 (M⁺).

Example 182

[1445] Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1446] 1) Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

[1447] Following the procedure of Example 1 (6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one andcyclopentylmethyl bromide {J. Org. Chem., 36, 3103 (1971)} were reactedto yield the title compound as yellow needles (yield: 72.0%).

[1448] Melting point: 56-66° C.

[1449]¹H NMR (400 MHz, CDCl₃) δ: 1.30-1.45 (2H, m), 1.53-1.65 (2H, m),1.65-1.80 (4H, m), 2.57 (1H, m), 3.95 (3H, s), 3.98 (3H, s), 4.24 (2H,d, J=7.8 Hz), 7.03 (1H, dd; J=8.5, 8.5 Hz), 7.50 (1H, d, J=8.8 Hz), 7.61(1H, d, J=10.2 Hz), 8.19 (1H, s).

[1450] 2) Preparation of4-carboxy-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1451] Following the procedure of Example 1 (7),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as ayellow powder (yield: 71.1%).

[1452] Melting point: 159-161° C.

[1453]¹H NMR (400 MHz, CDCl₃) δ: 1.33-1.45 (2H, m), 1.58-1.65 (2H, m),1.68-1.82 (4H, m) 2.57 (1H, m), 3.97 (3H, s), 4.32 (2H, d, J=7.6 Hz),7.06 (1H, dd, J=8.5, 8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.68 (1H, dd,J=12.2, 2.0 Hz), 8.61 (1H, s).

[1454] 3) Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1455] Following the procedure of Example 1 (8),4-carboxy-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:47.3%).

[1456] Melting point: 130-133° C.

[1457]¹H NMR (400 MHz, CDCl₃) δ: 1.30-1.42 (2H, m), 1.50-1.62 (2H, m),1.62-1.80 (4H, m), 2.54 (1H, m), 3.95 (3H, s), 4.19 (2H, d, J=7.6 Hz),4.71 (2H, s), 7.02 (1H, dd, J=8.5, 8.5 Hz), 7.51 (1H, d, J=8.5 Hz), 7.62(1H, dd, J=12.8, 1.5 Hz), 7.63 (1H, s).

[1458] 4) Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1459] Following the procedure of Example 1 (9),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as ayellow powder (yield: 75.3%).

[1460] Melting point: 108-116° C.

[1461]¹H NMR (400 MHz, CDCl₃) δ: 1.25-1.32 (2H, m), 1.32-1.45 (2H, m),1.65-1.77 (4H, m), 2.54 (1H, m), 3.17 (3H, s), 3.95 (3H, s), 4.19 (2H,d, J=7.6 Hz) 5.27 (2H, s), 7.03 (1H, dd, J=8.5, 8.5 Hz), 7.50 (1H, d,J=8.5 Hz), 7.62 (1H, dd, J=12.2, 2.2 Hz), 7.74 (1H, s).

[1462] 5) Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1463] Following the procedure of Example 1 (10),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reactedto yield the title compound as a yellow oil (yield: 61.4%).

[1464]¹H NMR (400 MHz, CDCl₃) δ: 1.32-1.42 (2H, m), 1.50-1.60 (2H, m),1.65-1.80 (4H, m), 2.38, 2.40 (each s, 3H in total), 2.54 (1H, m),2.60-2.75 (8H, m), 3.59 (2H, s), 3.95 (3H, s), 4.18 (2H, d, J=7.6 Hz),7.04 (1H, dd, J=8.5, 8.5 Hz), 7.54 (1H, d, J=8.5 Hz), 7.61 (1H, dd,J=8.5, 2.2 Hz), 7.72 (1H, s).

[1465] IR (Neat) cm⁻¹: 1652, 1608, 1523, 1439, 1286, 760.

[1466] Mass m/z: 414 (M⁺).

Example 183

[1467] Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[1468] Following the procedure of Example 4,2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield the titlecompound as a pale brown crystalline powder (yield: 59.6%).

[1469] Melting point: 234-236° C. (dec.)

[1470]¹H NMR (400 MHz, DMSO-d₆) δ: 1.28-1.40 (2H, m), 1.48-1.56 (2H, m),1.60-1.73 (4H, m), 2.46 (1H, m), 2.82 (3H, s), 3.50-3.75 (10H, m), 3.91(3H, s), 4.10 (2H, d, J=7.6 Hz), 7.31 (1H, dd, J=8.8, 8.8 Hz), 7.68-7.76(2H, m), 8.25 (1H, s).

[1471] IR (KBr) cm⁻¹: 1652, 1606, 1523, 1439, 1292, 764.

Example 184

[1472] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1473] Following the procedure of Example 1 (10),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethanolamine were reacted toyield the title compound as a yellow oil (yield: 54.9%).

[1474]¹H NMR (400 MHz, CDCl₃) δ: 1.30-1.45 (2H, m), 1.50-1.62 (2H, m),1.62-1.80 (4H, m), 2.53 (1H, m), 2.75-2.90 (4H, m), 3.70-3.75 (4H, m),3.80-3.85 (2H, m), 3.94 (3H, s), 4.20 (2H, d, J=7.6 Hz), 7.02 (1H, dd,J=8.5, 8.5 Hz), 7.56 (1H, d, J=8.5 Hz), 7.63 (1H, dd, J=8.5, 2.0 Hz),7.65 (1H, m).

[1475] IR (Neat) cm⁻¹: 1648, 1598, 1523, 1439, 1267, 728.

[1476] Mass m/z: 383 (M⁺-2H₂O).

Example 185

[1477] Preparation of2-cyclopentylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1478] Following the procedure of Example 7,2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted toyield the title compound as a yellow oil (yield: 63.7%).

[1479]¹H NMR (400 MHz, CDCl₃) δ: 1.30-1.45 (2H, m), 1.50-1.63 (2H, m),1.63-1.80 (4H, m), 2.43 (6H, s), 2.55 (1H, m), 3.61 (2H, s), 3.94 (3H,s), 4.19 (2H, d, J=7.6 Hz), 7.20 (1H, d, J=8.5, 8.5 Hz), 7.58 (1H, d,J=8.5 Hz), 7.65 (1H, dd, J=8.5, 2.2 Hz), 7.91 (1H, brs).

[1480] IR (Neat) cm⁻¹: 1652, 1608, 1523, 1438, 1288, 762.

[1481] Mass m/z: 359 (M⁺).

Example 186

[1482] Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

[1483] 1) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1484] Following the procedure of Example 1 (10),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl1-piperazinecarboxylate were reacted to yield the title compound as ayellow oil (yield: 78.8%).

[1485]¹H NMR (400 MHz, CDCl₃) δ: 1.35-1.43 (2H, m), 1.47 (9H, s),1.55-1.60 (2H, m) 1.65-1.75 (4H, m), 2.45-2.60 (5H, m), 3.45-3.55 (4H,m) 3.95 (3H, s), 4.18 (2H, d, J=7.6 Hz), 7.03 (1H, dd, J=8.5, 8.5 Hz),7.52 (1H, m), 7.62 (1H, d, J=12.4 Hz), 7.74 (1H, m).

[1486] 2) Preparation of2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

[1487] Following the procedure of Example 20,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted toyield the title compound as a yellow oil (yield: 88.0%).

[1488]¹H NMR (400 MHz, CDCl₃) δ: 1.33-1.43 (2H, m), 1.50-1.62 (2H, m),1.62-1.80 (4H, m), 2.55 (1H, m), 2.57-2.63 (4H, m), 3.00-3.02 (4H, m),3.56 (2H, brs), 3.95 (3H, s), 4.18 (2H, d, J=7.6 Hz), 7.04 (1H, dd,J=8.5, 8.5 Hz), 7.52 (1H, d, J=8.5 Hz), 7.62 (1H, dd, J=8.5, 2.2 Hz),7.73 (1H, s).

[1489] IR (Neat) cm⁻¹: 1652, 1608, 1523, 1439, 1287, 761.

[1490] Mass m/z: 400 (M⁺).

Example 187

[1491] Preparation of4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1492] Following the procedure of Example 24 (1),2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield a crudeproduct. Without purification, the crude product was reacted further inaccordance with the procedure of Example 24 (2) to yield the titlecompound as a yellow oil (yield: 53.7%).

[1493]¹H NMR (400 MHz, CDCl₃) δ: 1.30-1.45 (2H, m), 1.50-1.63 (2H, m),1.63-1.80 (4H, m), 2.54 (1H, m), 3.91 (2H, s), 3.93 (3H, s), 4.17 (2H,d, J=7.6 Hz) 7.01 (1H, dd, J=8.5, 8.5 Hz), 7.52 (1H, d, J=8.5 Hz), 7.62(1H, dd, J=8.5, 2.2 Hz), 7.71 (1H, brs).

[1494] IR (Neat) cm⁻¹: 3376, 1649, 1606, 1523, 1439, 1285, 761.

[1495] Mass m/z: 331 (M⁺).

Example 188

[1496] Preparation of4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one hydrochloride

[1497] Following the procedure of Example 4,4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as aslightly-yellow crystalline powder (yield: 59.0%).

[1498] Melting point: 193-196° C.

[1499]¹H NMR (400 MHz, DMSO-d₆) δ: 1.29-1.40 (2H, m), 1.45-1.57 (2H, m),1.60-1.70 (4H, m), 2.45 (1H, m), 3.91 (3H, s), 4.00 (2H, s), 4.12 (2H,d, J=7.6 Hz) 7.34 (1H, dd, J=8.5, 8.5 Hz), 7.69-7.72 (2H, m), 8.47 (1H,brs).

[1500] IR (KBr) cm⁻¹: 3436, 1656, 1617, 1521, 1438, 1295, 763.

Example 189

[1501] Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1502] 1) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

[1503] Following the procedure of Example 1 (6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and4-fluorobenzyl chloride were reacted to yield the title compound as aslightly-yellow crystalline powder (yield: 86.6%).

[1504]¹H NMR (400 MHz, CDCl₃) δ: 3.95 (3H, s), 3.97 (3H, s), 5.39 (2H,s), 7.00-7.06 (3H, m), 7.48-7.63 (4H, m), 8.19 (1H, s).

[1505] 2) Preparation of4-carboxy-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1506] Following the procedure of Example 1 (7),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as ayellow powder (yield: 97.7%).

[1507] Melting point: 222-224° C.

[1508]¹H NMR (400 MHz, CDCl₃) δ: 3.97 (3H, s), 5.47 (2H, s), 7.03-7.10(3H, m), 7.49-7.56 (3H, m), 7.67 (1H, dd, J=12.1, 2.2 Hz), 8.60 (1H, s).

[1509] 3) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1510] Following the procedure of Example 1 (8),4-carboxy-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:27.0%).

[1511] Melting point: 127-130° C.

[1512]¹H NMR (400 MHz, CDCl₃) δ: 3.95 (3H, s), 4.79 (2H, d, J=1.5 Hz),5.36 (2H, s), 6.98-7.05 (3H, m), 7.46-7.52 (3H, m), 7.61 (1H, dd,J=12.2, 2.2 Hz), 7.65 (1H, s).

[1513] 4) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1514] Following the procedure of Example 1 (9),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as apale yellow powder (yield: 49.4%).

[1515] Melting point: 125-133° C.

[1516]¹H NMR (400 MHz, CDCl₃) δ: 3.15 (3H, s), 3.95 (3H, s), 5.25 (2H,d, J=1.2 Hz), 5.35 (2H, s), 7.00-7.06 (3H, m), 7.45-7.55 (3H, m), 7.61(1H, dd, J=12.4, 2.2 Hz), 7.74 (1H, s).

[1517] 5) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1518] Following the procedure of Example 1 (10),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiprazine were reacted toyield the title compound as a slightly-brown crystalline powder (yield:45.8%).

[1519] Melting point: 112-113° C.

[1520]¹H NMR (400 MHz, CDCl₃) δ: 2.39 (3H, s), 2.60-2.90 (8H, m), 3.60(2H, s), 3.95 (3H, s), 5.34 (2H, s), 6.99-7.06 (3H, m), 7.47-7.51 (3H,m), 7.59 (1H, dd, J=12.4, 2.0 Hz), 7.71 (1H, s).

[1521] IR (KBr) cm⁻¹: 1651, 1608, 1518, 1439, 1289, 764.

[1522] Mass m/z: 440 (M⁺).

Example 190

[1523] Preparation of4-dimethylaminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1524] Following the procedure of Example 7,2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted toyield the title compound as a slightly-yellow crystalline powder (yield:60.8%).

[1525] Melting point: 127-129° C.

[1526]¹H NMR (400 MHz, CDCl₃) δ: 2.41 (6H, s), 3.58 (2H, s), 3.94 (3H,s), 5.35 (2H, s), 6.98-7.05 (3H, m), 7.46-7.52 (2H, m), 7.56 (1H, d,J=8.8 Hz), 7.64 (1H, dd, J=12.4, 2.2 Hz), 7.90 (1H, brs).

[1527] IR (KBr) cm⁻¹: 1652, 1612, 1519, 1439, 1291, 763.

[1528] Mass m/z: 385 (M⁺).

Example 191

[1529] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1530] Following the procedure of Example 1 (10),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethanolamine were reacted toyield the title compound as a yellow oil (yield: 66.1%).

[1531]¹H NMR (400 MHz, CDCl₃) δ: 2.70-2.92 (4H, m), 3.70-3.85 (6H, m),3.93 (3H, s), 5.35 (2H, s), 6.99-7.04 (3H, m), 7.45-7.50 (2H, m), 7.55(1H, d, J=8.3 Hz), 7.63 (1H, dd, J=12.4, 2.0 Hz), 7.90 (1H, m).

[1532] IR (Neat) cm⁻¹: 1652, 1606, 1520, 1435, 1281, 762.

[1533] Mass m/z: 385 (M⁺-CH₂OH)

Example 192

[1534] Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

[1535] 1) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-o ne

[1536] Following the procedure of Example 1 (10),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyl1-piperazinecarboxylate were reacted to yield the title compound as ayellow oil (yield: 78.8%).

[1537]¹H NMR (400 MHz, CDCl₃) δ: 1.46 (9H, s), 1.55-1.65 (4H, m),3.40-3.60 (4H, m), 3.95 (3H, s), 5.34 (2H, s), 6.96-7.05 (3H, m),7.47-7.50 (3H, m), 7.41 (1H, d, J=12.4 Hz), 7.74 (1H, brs).

[1538] 2) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

[1539] Following the procedure of Example 20,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted toyield the title compound as a pale yellow crystalline powder (yield:63.4%).

[1540] Melting point: 142-143° C.

[1541]¹H NMR (400 MHz, CDCl₃) δ: 2.50-2.60 (4H, m), 2.96-3.02 (4H, m),3.54 (2H, d, J=1.2 Hz), 3.95 (3H, s), 5.34 (2H, s), 6.98-7.06 (3H, m),7.46-7.53 (3H, m), 7.61 (1H, dd, J=12.5, 2.2 Hz), 7.74 (1H, br.s).

[1542] IR (KBr) cm⁻¹: 1652, 1609, 1523, 1437, 1290, 762.

[1543] Mass m/z: 426 (M⁺).

Example 193

[1544] Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[1545] Following the procedure of Example 4,2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield the title compoundas a colorless crystalline powder (yield: 76.9%).

[1546] Melting point: 153-156° C.

[1547]¹H NMR (400 MHz, DMSO-d₆) δ: 3.30-3.75(10H, m), 3.90 (3H, s), 5.33(2H, s), 7.15-7.21 (2H, m), 7.30 (1H, m), 7.43-7.49 (2H, m), 7.69-7.78(3H, m).

[1548] IR (KBr) cm⁻¹: 1660, 1609, 1524, 1439, 1292, 766.

Example 194

[1549] Preparation of4-aminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1550] Following the procedure of Example 24 (1),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield a crude product.Without purification, the crude product was reacted further inaccordance with the procedure of Example 24 (2) to yield the titlecompound as a pale brown crystalline powder (yield: 50.4%).

[1551] Melting point: 145-149° C.

[1552]¹H NMR (400 MHz, CDCl₃) δ: 3.92 (3H, s), 3.94 (2H, s), 5.31 (2H,s), 6.95-7.03 (3H, m), 7.40-7.52 (3H, m), 7.60 (1H, dd, J=12.5, 2.2 Hz),7.75 (1H, brs).

[1553] IR (KBr) cm⁻¹: 3391, 1648, 1606, 1519, 1437, 1292, 761.

[1554] Mass m/z: 357 (M⁺).

Example 195

[1555] Preparation of4-aminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one hydrochloride

[1556] Following the procedure of Example 4,4-aminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as aslightly-yellow crystalline powder (yield: 72.5%).

[1557] Melting point: 210-214° C.

[1558]¹H NMR (400 MHz, DMSO-d₆) δ: 3.91 (3H, s), 4.01 (2H, s), 5.35 (2H,s), 7.16-7.21 (2H, m), 7.34 (1H, dd, J=8.8, 8.8 Hz), 7.45-7.49 (2H, m),7.68-7.78 (2H, m), 8.29 (1H, s).

[1559] IR (KBr) cm⁻¹: 3429, 1653, 1612, 1522, 1439, 1292, 764.

Example 196

[1560] Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1561] 1) Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methoxycarbonyl-2H-pyridazin-3-one

[1562] Following the procedure of Example 1 (6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one andthe mesylate derivative of 3-(4-fluorophenyl)-1-propanol {J. Med. Chem.,19, 461 (1976)} were reacted to yield the title compound as a yellow oil(yield: 90.1%). The mesylate derivative was prepared in accordance withthe procedure of Example 1 (9).

[1563]¹H NMR (400 MHz, CDCl₃) δ: 2.16-2.26 (2H, m), 2.71 (2H, t, J=7.3Hz), 3.95 (3H, s), 3.98 (3H, s), 4.32 (2H, t, J=7.3 Hz), 6.93-7.06 (3H,m), 7.14-7.18 (2H, m), 7.49 (1H, m), 7.60 (1H, dd, J=13.2, 2.2 Hz), 8.17(1H, s).

[1564] 2) Preparation of4-carboxy-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one

[1565] Following the procedure of Example 1 (7),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methoxycarbonyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:89.2%).

[1566] Melting point: 185-187° C.

[1567]¹H NMR (400 MHz, CDCl₃) δ: 2.20-2.30 (2H, m), 2.74 (2H, t, J=7.3Hz), 3.97 (3H, s), 4.40 (2H, t, J=7.3 Hz), 6.94-7.17 (5H, m), 7.55 (1H,d, J=8.5 Hz), 7.66 (1H, dd, J=12.2, 2.2 Hz), 8.58 (1H, s).

[1568] 3) Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propy1]-4-hydroxymethyl-2H-pyridazin-3-one

[1569] Following the procedure of Example 1 (8),4-carboxy-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:37.0%).

[1570] Melting point: 130-133° C.

[1571]¹H NMR (400 MHz, CDCl₃) δ: 2.15-2.22 (2H, m), 2.71 (2H, t, J=7.3Hz), 3.95 (3H, s), 4.27 (2H, t, J=7.3 Hz), 4.70 (2H, d, J=1.2 Hz),6.93-7.06 (3H, m), 7.14-7.18 (2H, m), 7.50 (1H, d, J=8.8 Hz), 7.61 (1H,dd, J=12.7, 2.2 Hz), 7.63 (1H, s).

[1572] 4) Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propy1]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1573] Following the procedure of Example 1 (9),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:92.3%).

[1574] Melting point: 112-116° C.

[1575]¹H NMR (400 MHz, CDCl₃) δ: 2.15-2.25 (2H, m), 2.71 (2H, t, J=7.3Hz), 3.17 (3H, s), 3.95 (3H, s), 4.27 (2H, t, J=7.3 Hz), 5.25 (2H, d,J=1.2 Hz), 6.93-7.05 (3H, m), 7.14-7.18 (2H, m), 7.49 (1H, d, J=8.5 Hz),7.61 (1H, dd, J=13.4, 2.0 Hz), 7.72 (1H, s).

[1576] 5) Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propy1]-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1577] Following the procedure of Example 1 (10),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand 1-methylpiperazine were reacted to yield the title compound as ayellow oil (yield: 79.3%).

[1578]¹H NMR (400 MHz, CDCl₃) δ: 2.15-2.25 (2H, m), 2.41 (3H, s),2.60-2.75 (10H, m), 3.58 (2H, s), 3.75 (3H, s), 4.27 (2H, t, J=7.3 Hz),6.92-7.06 (3H, m), 7.14-7.18 (2H, m), 7.51 (1H, d, J=8.5 Hz), 7.60 (1H,dd, J=12.4, 2.0 Hz), 7.69 (1H, s).

[1579] IR (Neat) cm⁻¹: 1652, 1608, 1511, 1439, 1284, 758.

[1580] Mass m/z: 468 (M⁺).

Example 197

[1581] Preparation of4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one

[1582] Following the procedure of Example 7,6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand dimethylamine were reacted to yield the title compound as a paleyellow crystalline powder (yield: 61.8%).

[1583] Melting point: 97-100° C.

[1584]¹H NMR (400 MHz, CDCl₃) δ: 2.15-2.25 (2H, m), 2.43 (6H, s), 2.71(2H, t, J=7.3 Hz), 3.60 (2H, s), 3.94 (3H, s), 4.27 (2H, t, J=7.3 Hz),6.93-7.05 (3H, m), 7.15-7.18 (2H, m), 7.57 (1H, d, J=8.5 Hz), 7.64 (1H,dd, J=12.6, 2.2 Hz), 7.90 (1H, brs).

[1585] IR (KBr) cm⁻¹: 1653, 1611, 1510, 1436, 1296, 763.

[1586] Mass m/z: 413 (M⁺).

Example 198

[1587] Preparation of4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazi n-3-one

[1588] Following the procedure of Example 1 (10),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand diethanolamine were reacted to yield the title compound as a yellowoil (yield: 67.3%).

[1589]¹H NMR (400 MHz, CDCl₃) δ: 2.14-2.22 (2H, m), 2.70 (2H, t, J=7.6Hz), 2.75-2.95 (4H, m) 3.70-3.80 (6H, m), 3.94 (3H, s), 4.28 (2H, t,J=7.6 Hz), 6.93-7.05 (3H, m), 7.15-7.18 (2H, m), 7.56 (1H, m), 7.63 (1H,m), 7.85 (1H, m).

[1590] IR (Neat) cm⁻¹: 1645, 1601, 1510, 1439, 1277, 763.

[1591] Mass m/z: 473 (M⁺).

Example 199

[1592] Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

[1593] 1) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyr idazin-3-one

[1594] Following the procedure of Example 1 (10),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-oneand tert-butyl 1-piperazinecarboxylate were reacted to yield the titlecompound as a yellow oil (yield: 72.6%).

[1595]¹H NMR (400 MHz, CDCl₃) δ: 1.40 (9H, s), 2.07-2.16 (2H, m),2.40-2.50 (4H, m), 2.63 (2H, t, J=7.6 Hz), 3.36-3.46 (4H, m), 3.48 (2H,brs), 3.88 (3H, s), 4.20 (2H, t, J=7.6 Hz), 6.84-6.98 (3H, m), 7.07-7.11(2H, m), 7.43 (1H, d, J=8.1 Hz), 7.53 (1H, d, J=12.4 Hz), 7.65 (1H,brs).

[1596] 2) Preparation of6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propy1]-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

[1597] Following the procedure of Example 20,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 97.2%).

[1598]¹H NMR (400 MHz, CDCl₃) δ: 2.12-2.22 (2H, m), 2.50-2.60 (4H, m),2.71 (2H, t, J=7.3 Hz), 2.92-3.02 (4H, m), 3.53 (2H, s), 3.95 (3H, s),4.27 (2H, t, J=7.3 Hz), 6.91-7.06 (3H, m), 7.15-7.18 (2H, m), 7.51 (1H,d, J=8.8 Hz), 7.61 (1H, dd, J=12.5, 2.2 Hz), 7.73 (1H, s).

[1599] IR (Neat) cm⁻¹: 1650, 1607, 1510, 1439, 1275, 758.

[1600] Mass m/z: 454 (M⁺)

Example 200

[1601] Preparation of4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one

[1602] Following the procedure of Example 24 (1),6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to a crudeproduct. Without purification, the crude product was reacted inaccordance with the procedure of Example 24 (2) to yield the titlecompound as a pale yellow crystalline powder (yield: 41.7%).

[1603] Melting point: 82-84° C.

[1604]¹H NMR (400 MHz, CDCl₃) δ: 2.12-2.22 (2H, m), 2.70 (2H, t, J=7.6Hz), 3.89 (2H, s), 3.94 (3H, s), 4.27 (2H, t, J=7.6 Hz), 6.93-7.04 (3H,m), 7.15-7.18 (2H, m), 7.51 (1H, d, J=7.3 Hz), 7.61 (1H, dd, J=12.4, 2.0Hz), 7.67 (1H, s).

[1605] IR (KBr) cm⁻¹: 3366, 1651, 1605, 1509, 1436, 1273, 764.

[1606] Mass m/z: 385 (M⁺).

Example 201

[1607] Preparation of4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one hydrochloride

[1608] Following the procedure of Example 4,4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one was reacted to yield the title compoundas a slightly-yellow crystalline powder (yield: 73.1%).

[1609] Melting point: 160-165° C.

[1610]¹H NMR (400 MHz, DMSO-d₆) δ: 2.05-2.15 (2H, m), 2.66 (2H, t, J=7.3Hz), 3.92 (3H, s), 3.99 (2H, s), 4.19 (2H, t, J=7.3 Hz), 7.05-7.12 (2H,m), 7.23-7.30 (0.2H, m), 7.34 (1H, dd, J=8.8, 8.8 Hz), 7.66-7.76 (2H,m), 8.25 (1H, s).

[1611] IR (KBr) cm⁻¹: 3430, 1652, 1515, 1436, 1269, 763.

Example 202

[1612] Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1613] 1) Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

[1614] Following the procedure of Example 1 (6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and4-chlorobenzyl chloride were reacted to yield the title compound asyellow needles (yield: 97.6%).

[1615] Melting point: 170.5-171.1° C.

[1616]¹H NMR (400 MHz, CDCl₃) δ: 3.95 (3H, s), 3.99 (3H, s), 5.38((2H,s), 7.03 (1H, dd, J=8.5, 8.5 Hz), 7.31 (2H, d, J=8.5 Hz), 7.47 (2H, d,J=8.5 Hz), 7.49 (1H, m), 7.60 (1H, dd, J=12.2, 2.2 Hz), 8.20 (1H, s).

[1617] IR (KBr) cm⁻¹: 1723, 1670, 1526, 1271, 1128.

[1618] Mass m/z: 402 (M⁺), 404 ((M⁺).

[1619] 2) Preparation of4-carboxy-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1620] Following the procedure of Example 1 (7),2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as apale yellow crystalline powder (yield: 96.0%).

[1621] Melting point: 228.3-229.1° C.

[1622]¹H NMR (400 MHz, CDCl₃) δ: 3.97 (3H, s), 5.46 (2H, s), 7.07 (1H,dd, J=8.5, 8.5 Hz), 7.35 (2H, d, J=8.3 Hz), 7.46 (2H, d, J=8.3 Hz), 7.55(1H, d, J=8.4 Hz), 7.67 (1H, dd, J=12.2, 2.2 Hz), 8.61 (1H, s).

[1623] IR (KBr) cm⁻¹: 1745, 1635, 1456, 1447, 1431, 1298, 1273.

[1624] Mass m/z: 388 (M⁺), 390 (M⁺)

[1625] 3) Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1626] Following the procedure of Example 1 (8),4-carboxy-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:20.4%).

[1627] Melting point: 164.6-165.3° C.

[1628]¹H NMR (400 MHz, CDCl₃) δ: 3.94 (3H, s), 4.69 (2H, s), 5.34 (2H,s), 7.01 (1H, dd, J=8.5, 8.5 Hz), 7.30 (2H, d, J=8.5 Hz), 7.42 (2H, d,J=8.5 Hz), 7.50 (1H, m), 7.63 (1H, dd, J=12.4, 2.2 Hz), 7.67 (1H, s).

[1629] IR (KBr) cm⁻¹: 3373, 1653, 1610, 1527, 1291, 1135.

[1630] Mass m/z: 374 (M⁺), 376 (M⁺)

[1631] 4) Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1632] Following the procedure of Example 1 (9),2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as paleyellow needles (yield: 81.6%).

[1633] Melting point: 156.5-157.4° C.

[1634]¹H NMR (400 MHz, CDCl₃) δ: 3.15 (3H, s), 3.95 (3H, s), 5.22 (2H,d, J=1.5 Hz), 5.35 (2H, s), 7.03 (1H, dd, J=8.5, 8.5 Hz), 7.31 (2H, d,J=8.5 Hz), 7.42 (2H, d, J=8.5 Hz), 7.49 (1H, m), 7.61 (1H, dd, J=12.2,2.2 Hz), 7.75 (1H, s).

[1635] IR (KBr) cm⁻¹: 1658, 1616, 1358, 1183, 1017.

[1636] 5) Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1637] Following the procedure of Example 1 (10),2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reactedto yield the title compound as pale brown prisms (yield: 39.5%).

[1638] Melting point: 128.7-130.2° C.

[1639]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, s), 2.52 (4H, brs), 2.60 (4H,brs), 3.55 (2H, s), 3.95 (3H, s), 5.34 (2H, s), 7.04 (1H, dd, J=8.5, 8.5Hz), 7.30 (2H, d, J=8.5 Hz), 7.43 (2H, d, J=8.5 Hz), 7.51 (1H, m) 7.60(1H, dd, J=12.4, 2.0 Hz), 7.73 (1H, s).

[1640] IR (KBr) cm⁻¹: 1652, 1607, 1524, 1516, 1438, 1288, 1135.

Example 203

[1641] Preparation of2-(4-chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1642] Following the procedure of Example 7,2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted toyield the title compound as a slightly-yellow crystalline powder (yield:74.7%).

[1643] Melting point: 95.3-96.7° C.

[1644]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (6H, s), 3.47 (2H, d, J=1.2 Hz),3.94 (3H, s), 5.34 (2H, s), 7.01 (1H, dd, J=8.5, 8.5 Hz), 7.30 (2H, d,J=8.5 Hz), 7.44 (2H, d, J=8.5 Hz), 7.53 (1H, ddd, J=8.5, 2.0, 1.2 Hz),7.62 (1H, dd, J=12.4, 2.2 Hz), 7.74 (1H, s).

[1645] IR (KBr) cm⁻¹: 1652, 1609, 1524, 1515, 1436, 1289, 1264, 1017.

[1646] Mass m/z: 401 (M⁺), 403 (M⁺)

Example 204

[1647] Preparation of2-(4-chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onehydrochloride

[1648] Following the procedure of Example 4,2-(4-chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound asa slightly-yellow crystalline powder (yield: 59.7%).

[1649] Melting point: 193.4-194.7° C.

[1650]¹H NMR (400 MHz, CD₃OD) δ: 2.96 (6H, s), 3.94 (3H, s), 4.33 (2H,s), 5.43 (2H, s), 7.22 (1H, dd, J=8.5, 8.5 Hz), 7.36 (2H, d, J=8.5 Hz),7.46 (2H, d, J=8.5 Hz), 7.67-7.72 (2H, m), 8.20 (1H, s).

[1651] IR (KBr) cm⁻¹: 1655, 1616, 1529, 1327, 1279.

Example 205

[1652] Preparation of4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1653] 1) Preparation of2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one

[1654] Following the procedure of Example 24 (1),2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the titlecompound as slightly-yellow needles (yield: 75.4%).

[1655] Melting point: 212.5-213.9° C.

[1656]¹H NMR (400 MHz, CDCl₃) δ: 3.90 (3H, s), 4.88 (2H, d, J=0.73 Hz),5.35 (2H, s), 6.95 (1H, dd, J=8.5, 8.5 Hz), 7.29 (1H, s), 7.31 (2H, d,J=8.5 Hz), 7.36 (1H, m), 7.44 (2H, d, J=8.5 Hz), 7.47 (1H, dd, J=12.2,2.0 Hz), 7.76-7.81 (2H, m), 7.89-7.94 (2H, m).

[1657] IR (KBr) cm⁻¹: 1773, 1713, 1651, 1610, 1522, 1439, 1419, 1393,1300.

[1658] Mass m/z: 503 (M⁺), 505 (M⁺).

[1659] 2) Preparation of4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1660] Following the procedure of Example 24 (2),2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-phthalimidomethyl-2H-pyridazin-3-one was reacted to yield the title compound asslightly-yellow needles (yield: 48.8%).

[1661] Melting point: 128.5-131.4° C.

[1662]¹H NMR (400 MHz, CDCl₃) δ: 3.88 (2H, s), 3.94 (3H, s), 5.34 (2H,s), 7.02 (1H, dd, J=8.5, 8.5 Hz), 7.30 (2H, d, J=8.5 Hz), 7.43 (2H, d,J=8.5 Hz), 7.51 (1H, ddd, J=8.5, 2.2, 1.2 Hz), 7.61 (1H, dd, J=12.4, 2.2Hz), 7.69 (1H, t, J=1.2 Hz).

[1663] IR (KBr) cm⁻¹: 3392, 1615, 1604, 1520, 1434, 1292, 1133, 1018.

[1664] Mass m/z: 373 (M⁺), 375 ((M⁺)

Example 206

[1665] Preparation of4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one hydrochloride

[1666] Following the procedure of Example 4,4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as aslightly-yellow crystalline powder (yield: 66.0%).

[1667] Melting point: 202.0-205.5° C.

[1668]¹H NMR (400 MHz, CD₃OD) δ: 3.94 (3H, s), 4.13 (2H, s), 5.41 (2H,s), 7.21 (1H, dd, J=8.8, 8.8 Hz), 7.35 (2H, d, J=8.5 Hz), 7.46 (2H, d,J=8.5 Hz), 7.65-7.71 (2H, m), 8.08 (1H, s).

[1669] IR (KBr) cm⁻¹: 2940, 1655, 1616, 1526, 1439, 1292.

Example 207

[1670] Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1671] 1) Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

[1672] Following the procedure of Example 1 (6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3,4-difluorobenzyl bromide were reacted to yield the title compound as ayellow crystalline powder (yield: 92.1%).

[1673] Melting point: 144-148° C.

[1674]¹H NMR (400 MHz, CDCl₃) δ: 3.96 (3H, s), 3.97 (3H, s), 5.35 (2H,s), 7.04 (1H, dd, J=8.5, 8.5 Hz), 7.12 (1H, m), 7.28 (1H, m), 7.36 (1H,m), 7.50 (1H, m) 7.60 (1H, dd, J=12.2, 1.5 Hz), 8.21 (1H, s).

[1675] IR (KBr) cm⁻¹: 1756, 1656, 1609, 1518, 1439, 1239, 1293, 1278,1204.

[1676] Mass m/z: 404 (M⁺).

[1677] 2) Preparation of4-carboxy-2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1678] Following the procedure of Example 1 (7),2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound asa yellow crystalline powder (yield: 97.6%).

[1679] Melting point: 196.4-197.0° C.

[1680]¹H NMR (400 MHz, CDCl₃) δ: 3.97 (3H, s), 5.44 (2H, s), 7.07 (1H,dd, J=8.5, 8.5 Hz), 7.17 (1H, m), 7.27 (1H, m), 7.36 (1H, ddd, J=8.1,8.1, 2.2 Hz), 7.56 (1H, m), 7.66 (1H, dd, J=12.2, 2.2 Hz), 8.61 (1H, s),13.83 (1H, s).

[1681] IR (KBr) cm⁻¹: 1757, 1636, 1567, 1518, 1463, 1440, 1284.

[1682] Mass m/z: 390 (M⁺).

[1683] 3) Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1684] Following the procedure of Example 1 (8),4-carboxy-2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound asslightly-yellow neeldes (yield: 7.7%).

[1685] Melting point: 154.1-155.5° C.

[1686]¹H NMR (400 MHz, CDCl₃) δ: 2.85 (1H, t, J=5.6 Hz), 3.95 (3H, s),4.71 (2H, d, J=5.6 Hz), 5.33 (2H, s), 7.03 (1H, dd, J=8.5, 8.5 Hz), 7.12(1H, m), 7.23 (1H, m), 7.31 (1H, ddd, J=11.0, 7.6, 2.2 Hz), 7.51 (1H,ddd, J=8.5, 2.2, 1.2 Hz), 7.61 (1H, dd, J=12.4, 2.2 Hz), 7.68 (1H, t,J=1.2 Hz).

[1687] IR (KBr) cm⁻¹: 3390, 1648, 1602, 1518, 1440, 1285, 1141.

[1688] Mass m/z: 376 (M⁺).

[1689] 4) Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1690] Following the procedure of Example 1 (9),2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound asslightly-yellow neeldes (yield: 91.5%).

[1691] Melting point: 145.6-146.6° C.

[1692]¹H NMR (400 MHz, CDCl₃) δ: 3.16 (3H, s), 3.96 (3H, s), 5.26 (2H,d, J=1.2 Hz), 5.32 (2H, s), 7.04 (1H, dd, J=8.5 8.5 Hz), 7.13 (1H, m),7.23 (1H, m), 7.32 (1H, m), 7.50 (1H, m), 7.61 (1H, dd, J=12.4, 2.2 Hz),7.76 (1H, t, J=1.2 Hz).

[1693] IR (KBr) cm⁻¹: 1656, 1612, 1522, 1440, 1352, 1277, 1163.

[1694] Mass m/z: 454 (M⁺).

[1695] 5) Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1696] Following the procedure of Example 1 (10),2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine werereacted to yield the title compound as slightly-yellow neeldes (yield:55.0%).

[1697] Melting point: 135.4-136.0° C.

[1698]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, s), 2.51 (4H, brs), 2.62 (4H,brs), 3.56 (2H, d, J=1.5 Hz), 3.95 (3H, s), 5.31 (2H, s), 7.04 (1H, dd,J=8.5, 8.5 Hz), 7.11 (1H, m), 7.23 (1H, m), 7.32 (1H, ddd, J=11.0, 7.6,2.0 Hz) 7.52 (1H, ddd, J=8.5, 2.2, 1.2 Hz), 7.59 (1H, dd, J=12.2, 2.2Hz), 7.74 (1H, t, J=1.2 Hz).

[1699] IR (KBr) cm⁻¹: 1652, 1608, 1522, 1437, 1291, 1273, 1139.

[1700] Mass m/z: 458 (M⁺).

Example 208

[1701] Preparation of2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1702] Following the procedure of Example 7,2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted toyield the title compound as slightly-yellow needles (yield: 77.1%).

[1703] Melting point: 129.9-130.4° C.

[1704]¹H NMR (400 MHz, CDCl₃) δ: 2.35 (6H, s), 3.49 (2H, s), 3.95 (3H,s), 5.32 (2H, s), 7.02 (1H, dd, J=8.5, 8.5 Hz), 7.11 (1H, m), 7.24 (1H,m), 7.32 (1H, ddd, J=11.0, 7.6, 2.2 Hz), 7.54 (1H, ddd, J=8.5, 2.2, 1.2Hz), 7.62 (1H, dd, J=12.4, 2.2 Hz), 7.77 (1H, s).

[1705] IR (KBr) cm⁻¹: 1653, 1610, 1519, 1437, 1291, 1283, 1267, 1138,1114.

[1706] Mass m/z: 403 (M⁺).

Example 209

[1707] Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1708] 1) Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

[1709] Following the procedure of Example 1 (6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and4-chlorocinnamyl chloride were reacted to yield the title compound as apale yellow crystalline powder (yield: 51.1%).

[1710] Melting point: 117-119° C.

[1711]¹H NMR (400 MHz, CDCl₃) δ: 3.95 (3H, s), 3.98 (3H, s), 5.02 (2H,dd, J=6.8, 1.2 Hz), 6.43 (1H, dt, J=15.9, 6.8 Hz), 6.70 (1H, d, J=15.9Hz), 7.03 (1H, dd, J=8.5, 8.5 Hz), 7.25 (2H, d, J=8.8 Hz), 7.31 (2H, d,J=8.8 Hz), 7.50 (1H, dt, J=8.5, 2.2 Hz), 7.62 (1H, dd, J=12.2, 2.2 Hz),8.22 (1H, s).

[1712] IR (KBr) cm⁻¹: 1724, 1709, 1667, 1506, 1291, 1236, 1126, 831.

[1713] Mass m/z: 412 (M⁺), 414 (M⁺).

[1714] 2) Preparation of4-carboxy-2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1715] Following the procedure of Example 1 (7),2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one was reacted to yield the title compound as apale yellow crystalline powder (yield: 98.2%).

[1716] Melting point: 217.2-218.5° C.

[1717]¹H NMR (400 MHz, CDCl₃) δ: 3.97 (3H, s), 5.10 (2H, d, J=6.8 Hz),6.39 (1H, dt, J=15.9, 6.8 Hz), 6.75 (1H, d, J=15.9 Hz), 7.06 (1H, dd,J=8.5, 8.5 Hz), 7.30 (2H, d, J=8.5 Hz), 7.34 (2H, d, J=8.5 Hz), 7.57(1H, m), 7.69 (1H, dd, J=12.2, 2.2 Hz), 8.63 (1H, s), 13.99 (1H, s).

[1718] IR (KBr) cm⁻¹: 3059, 1744, 1629, 1523, 1480, 1438, 1426, 1296,1272.

[1719] Mass m/z: 414 (M⁺), 416 (M⁺)

[1720] 3) Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1721] Following the procedure of Example 1 (8),4-carboxy-2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow crystals (yield:17.0%).

[1722] Melting point: 158.2-160.5° C.

[1723]¹H NMR (400 MHz, CDCl₃) δ: 2.95 (1H, t, J=5.9 Hz), 3.94 (3H, s),4.73 (2H, dd, J=5.9, 1.2 Hz), 4.98 (2H, dd, J=6.6, 1.2 Hz), 6.40 (1H,dt, J=15.9, 6.6 Hz), 6.67 (1H, d, J=15.9 Hz), 7.02 (1H, dd, J=8.5, 8.5Hz), 7.27 (2H, d, J=8.5 Hz), 7.32 (2H, d, J=8.5 Hz), 7.51 (1H, ddd,J=8.8, 2.2, 1.2 Hz), 7.63 (1H, dd, J=12.4, 2.2 Hz), 7.67 (1H, t, J=1.2Hz).

[1724] IR (KBr) cm⁻¹: 3392, 1648, 1603, 1523, 1440, 1284, 1273, 1140.

[1725] Mass m/z: 400 (M⁺), 402 (M⁺)

[1726] 4) Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1727] Following the procedure of Example 1 (9),2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound aspale yellow neeldes (yield: 90.7%).

[1728] Melting point: 135.8-136.4° C.

[1729]¹H NMR (400 MHz, CDCl₃) δ: 3.17 (3H, s), 3.95 (3H, s), 4.98 (2H,dd, J=6.6, 0.98 Hz), 5.28 (2H, d, J=1.5 Hz), 6.39 (1H, dt, J=15.9, 6.6Hz), 6.67 (1H, d, J=15.9 Hz), 7.03 (1H, dd, J=8.5, 8.5 Hz), 7.27 (2H, d,J=8.5 Hz), 7.32 (2H, d, J=8.5 Hz), 7.50 (1H, m), 7.62 (1H, dd, J=12.2,2.2 Hz), 7.77 (1H, t, J=1.2 Hz).

[1730] IR (KBr) cm⁻¹: 1660, 1615, 1523, 1436, 1360, 1335, 1287, 1273,1179.

[1731] Mass m/z: 478 (M⁺), 480 (M⁺).

[1732] 5) Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1733] Following the procedure of Example 1 (10),2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiperazine were reactedto yield the title compound as pale brown neeldes (yield: 66.3%).

[1734] Melting point: 123.9-125.5° C.

[1735]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, s), 2.52 (4H, brs), 2.62 (4H,brs), 3.58 (2H, d, J=1.2 Hz), 3.95 (3H, s), 4.98 (2H, dd, J=6.8, 1.2Hz), 6.41 (1H, dt, J=15.9, 6.8 Hz), 6.66 (1H, d, J=15.9 Hz), 7.04 (1H,dd, J=8.5, 8.5 Hz), 7.26 (2H, d, J=8.5 Hz), 7.32 (2H, d, J=8.5 Hz), 7.53(1H, ddd, J=8.5, 2.0, 1.2 Hz), 7.62 (1H, dd, J=12.4, 2.2 Hz), 7.75 (1H,t, J=1.2 Hz).

[1736] IR (KBr) cm⁻¹: 1647, 1606, 1522, 1439, 1282, 1270.

[1737] Mass m/z: 482 (M⁺), 484 (M⁺)

Example 210

[1738] Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one

[1739] Following the procedure of Example 1 (10),2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-piperazineethanol werereacted to yield the title compound as slightly-yellow needles (yield:65.1%).

[1740] Melting point: 133.1-134.9° C.

[1741]¹H NMR (400 MHz, CDCl₃) δ: 2.57-2.62(1H, m), 3.58 (2H, d, J=1.2Hz), 3.63 (2H, t, J=5.4 Hz), 3.94 (3H, s), 4.97 (2H, d, J=6.6 Hz), 6.41(1H, dt, J=15.9, 6.6 Hz), 6.67 (1H, d, J=15.9 Hz), 7.03 (1H, dd, J=8.5,8.5 Hz), 7.26 (2H, d, J=8.5 Hz), 7.32 (2H, d, J=8.5 Hz), 7.53 (1H, m),7.61 (1H, dd, J=12.4, 2.2 Hz), 7.75 (1H, s).

[1742] IR (KBr) cm⁻¹: 3451, 1647, 1605, 1523, 1438, 1285, 1274, 1137.

[1743] Mass m/z: 478 (M⁺), 480 (M⁺).

Example 211

[1744] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one

[1745] 1) Preparation of4-bromomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1746] 2-Cyclopropyl-methyl-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one (185 mg, 0.61 mmol), carbon tetrabromide(404 mg, 1.2 mmol) and pyridine (48 mg, 0.61 mmol) were dissolved intetrahydrofuran (3 mL), and under ice-cold stirring, a solution oftriphenylphosphine (319 mg, 1.2 mmol) in tetrahydrofuran (3 mL) wasadded. Under ice cooling, the mixture was stirred for 1 hour, andfurther stirred overnight at room temperature. Insoluble materials werefiltered off, the solvent was distilled off under reduced pressure, andthe residue was isolated and purified by column chromatography on silicagel (hexane/ethyl acetate=2/1) to yield the title compound as a yellowpowder (yield: 155 mg, 69.5%).

[1747]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.60 (4H, m), 1.58 (1H, m), 3.95(3H, s), 4.12 (2H, d, J=7.3 Hz), 4.49 (2H, s), 7.03 (1H, dd, J=8.5, 8.5Hz), 7.50 (1H, m), 7.60 (1H, dd, J=13.4, 2.2 Hz), 7.77 (1H, s).

[1748] 2) Preparation of2-cyclopropylmethyl-4-[2,2-di(tert-butoxycarbonyl)ethyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-oneAfter 55% sodium hydride (322 mg, 7.38 mmol) was added to a solution ofdi-tert-butyl malonate (970 mg, 4.48 mmol) in N,N-dimethylformamide (10mL), 4-bromomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one (1.8 g, 4.90 mmol) was added under ice-coldstirring. The reaction mixture was stirred at room temperature for 1hour, poured into water, and extracted with ethyl acetate. The extractwas washed with brine and dried over anhydrous sodium sulfate. Thesolvent was distilled off under reduced pressure. The residue wasisolated and purified by chromatography on silica gel (hexane/ethylacetate=3/1) to yield the title compound as a yellow powder (yield: 1.39mg, 61.8%).

[1749]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.50 (2H, m), 0.50-0.58 (2H, m),1.41 (18H, s), 1.56 (1H, m), 3.12 (2H, d, J=7.8 Hz), 3.87 (1H, t, J=7.8Hz), 3.94 (3H, s), 4.09 (2H, d, J=7.8 Hz), 7.01 (1H, dd, J=8.5, 8.5 Hz),7.43 (1H, d, J=8.5 Hz), 7.50 (1H, s), 7.57 (1H, dd, J=12.4, 2.2 Hz).

[1750] 3) Preparation of4-(2-carboxyethyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one Trifluoroacetic acid (21 mL) was addedto2-cyclopropylmethyl-4-[2,2-di(tert-butoxycarbonyl)ethyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one(1.39 g, 2.77 mmol), and the mixture was stirred at room temperature for30 minutes. The solvent was distilled off under reduced pressure, andtoluene was added further, followed by azeotropic boiling. The residuewas heated at 190 to 200° C. for 30 minutes under a nitrogen atmosphereto yield the title compound as a pale brown powder (yield: 907 mg,94.7%).

[1751]¹H NMR (400 MHz, CDCl₃) δ: 0.45-0.50 (2H, m), 0.50-0.60 (2H, m),1.41 (1H, m), 2.80 (2H, t, J=7.1 Hz), 2.97 (2H, t, J=7.1 Hz), 3.94 (3H,s), 4.10 (2H, d, J=7.3 Hz), 7.02 (1H, dd, J=8.5, 8.5 Hz), 7.47 (1H, d,J=8.5 Hz), 7.55 (1H, s), 7.59 (1H, dd, J=12.4, 2.2 Hz).

[1752] 4) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-one

[1753] Following the procedure of Example 1 (8),4-(2-carboxyethyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as abrown oil (yield: 82.9%).

[1754]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.52 (2H, m), 0.52-0.60 (2H, m),1.42 (1H, m), 1.88-1.94 (2H, m), 2.81 (2H, t, J=6.1 Hz), 3.63 (2H, t,J=5.9 Hz), 3.95 (3H, s), 4.12 (2H, d, J=7.3 Hz), 7.02 (1H, dd, J=8.5,8.5 Hz), 7.50 (1H, m), 7.52 (1H, s), 7.60 (1H, dd, J=12.4, 2.2 Hz).

[1755] 5) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one

[1756] Following the procedure of Example 1 (9),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-one was reacted to yield the title compound asa pale brown powder (yield: 82.0%).

[1757]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.51 (2H, m), 0.51-0.60 (2H, m),1.41 (1H, m), 2.13-2.21 (2H, m), 2.80 (2H, t, J=7.1 Hz), 3.04 (3H, s),3.94 (3H, s), 4.09 (2H, d, J=7.3 Hz), 4.31 (2H, t, J=6.1 Hz), 7.02 (1H,dd, J=8.5, 8.5 Hz), 7.49 (1H, d, J=8.5 Hz), 7.53 (1H, s), 7.61 (1H, dd,J=12.4, 2.2 Hz).

[1758] 6) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one

[1759] Following the procedure of Example 1 (10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and 1-methylpiperazine werereacted to yield the title compound as a yellow oil (yield: 62.0%).

[1760]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.50 (2H, m), 0.50-0.60 (2H, m),1.41 (1H, m), 1.90-2.00 (2H, m), 2.45 (3H, s), 2.50-3.00 (12H, m), 3.94(3H, s), 4.08 (2H, d, J=7.3 Hz), 7.02 (1H, dd, J=8.5, 8.5 Hz), 7.48 (1H,s), 7.50 (1H, d, J=8.5 Hz), 7.70 (1H, dd, J=12.3, 2.0 Hz).

[1761] IR (Neat) cm⁻¹: 1648, 1607, 1524, 1286, 1122, 1022, 755.

[1762] Mass m/z: 414 (M⁺)

Example 212

[1763] Preparation of2-cyclopropylmethyl-4-(3-dimethylaminopropyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1764] Following the procedure of Example 7,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and dimethylamine were reactedto yield the title compound as a yellow powder (yield: 64.7%).

[1765]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.50 (2H, m), 0.53-0.60 (2H, m),1.40 (1H, m), 2.24-2.35 (2H, m), 2.75-2.80 (2H, m), 2.79 (6H, s), 3.03(2H, t, J=7.3 Hz), 3.94 (3H, s), 4.08 (2H, d, J=7.1 Hz), 7.04 (1H, dd,J=8.5, 8.5 Hz), 7.57 (1H, d, J=8.5 Hz), 7.65 (1H, dd, J=12.4, 2.2 Hz),7.72 (1H, s).

[1766] IR (Neat) cm⁻¹: 1649, 1608, 1524, 1288, 1122, 1022, 761.

[1767] Mass m/z: 359 (M⁺).

Example 213

[1768] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one

[1769] 1) Preparation of2-cyclopropylmethyl-4-[3-(4-tert-butoxycarbonyl-1-piperazinyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazi n-3-one

[1770] Following the procedure of Example 1 (10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and tert-butyl1-piperazinecarboxylate were reacted to yield the title compound as ayellow oil (yield: 76.9%).

[1771]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.50 (2H, m), 0.52-0.60 (2H, m),1.44 (1H, m), 1.46 (9H, s), 2.00-2.40 (2H, m), 2.50-2.80 (6H, m),3.50-3.75 (6H, m), 3.94 (3H, s), 4.08 (2H, d, J=7.1 Hz), 7.02 (1H, dd,J=8.5, 8.5 Hz), 7.47-7.65 (3H, m)

[1772] 2) Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one

[1773] Following the procedure of Example 20,2-cyclopropylmethyl-4-[3-(4-tert-butoxycarbonyl-1-piperazinyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reactedto yield the title compound as a yellow oil (yield: 78.9%).

[1774]¹H NMR (400 MHz, CDCl₃) δ: 0.43-0.50 (2H, m), 0.50-0.59 (2H, m),1.42 (1H, m), 1.82-1.92 (2H, m), 2.40-2.50 (6H, m), 2.68 (2H, t, J=7.6Hz), 2.93-2.95 (4H, m), 3.94 (3H, s), 4.08 (2H, d, J=7.3 Hz), 7.01 (1H,dd, J=8.5, 8.5 Hz), 7.45 (1H, s), 7.48 (1H, d, J=8.5 Hz), 7.59 (1H, dd,J=11.4, 2.0 Hz).

[1775] IR (Neat) cm⁻¹: 1648, 1607, 1523, 1288, 1122, 1023, 760.

[1776] Mass m/z: 400 (M⁺).

Example 214

[1777] Preparation of2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-onedihydrochloride

[1778] Following the procedure of Example 4,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one was reacted to yield the titlecompound as a slightly-yellow crystalline powder (yield: 83.1%).

[1779] Melting point: 174-178° C.

[1780]¹H NMR (400 MHz, DMSO-d₆) δ: 0.39-0.45 (2H, m), 0.45-0.55 (2H, m),1.32 (1H, m), 2.00-2.25 (2H, m), 2.62-2.66 (2H, m), 3.20-3.85 (10H, m),3.90 (3H, s), 4.01 (2H, d, J=7.1 Hz), 7.28 (1H, dd, J=8.8, 8.8 Hz),7.72-7.80 (2H, m), 7.96 (1H, s).

[1781] IR (KBr) cm⁻¹: 1647, 1604, 1523, 1297, 1123, 1020, 762.

Example 215

[1782] Preparation of4-[3-[N,N-bis(2-hydroxyethyl)amino]propyl]-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1783] Following the procedure of Example 1 (10),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and diethanolamine were reactedto yield the title compound as a yellow oil (yield: 13.1%).

[1784]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.50 (2H, m), 0.50-0.60 (2H, m),1.41 (1H, m), 2.10-2.20 (2H, m), 2.76 (2H, t, J=7.3 Hz), 3.00-3.15 (6H,m), 3.87-3.92 (4H, m), 3.94 (3H, s), 4.08 (2H, d, J=7.3 Hz), 7.02 (1H,dd, J=8.5, 8.5 Hz), 7.53 (1H, d, J=8.5 Hz), 7.60 (1H, s), 7.62 (1H, dd,J=12.4, 2.2 Hz).

[1785] IR (Neat) cm⁻¹: 1645, 1602, 1524, 1288, 1123, 1024, 756.

[1786] Mass m/z: 400 (M⁺-CH₂OH).

Example 216

[1787] Preparation of4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[1788] Following the procedure of Example 24 (1),2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one was reacted to yield a crudeproduct. Without purification, the crude product was reacted further inaccordance with the procedure of Example 24 (2) to yield the titlecompound as a yellow oil (yield: 67.8%).

[1789]¹H NMR (400 MHz, CDCl₃) δ: 0.44-0.50 (2H, m), 0.50-0.60 (2H, m),1.41 (1H, m), 1.84-1.96 (2H, m), 2.67-2.80 (4H, m), 2.87 (2H, t, J=6.1Hz), 3.94 (3H, s), 4.08 (2H, d, J=7.3 Hz), 7.01 (1H, dd, J=8.5, 8.5 Hz),7.49 (1H, d, J=8.5 Hz), 7.50 (1H, s), 7.59 (1H, dd, J=12.4, 2.2 Hz).

[1790] IR (Neat) cm⁻¹: 3370, 1648, 1606, 1523, 1289, 1122, 1023, 760.

[1791] Mass m/z: 331 (M⁺).

Example 217

[1792] Preparation of4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one hydrochloride

[1793] Following the procedure of Example 4,4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as aslightly-yellow crystalline powder (yield: 70.6%).

[1794] Melting point: 183-185° C.

[1795]¹H NMR (400 MHz, DMSO-d₆) δ: 0.40-0.45 (2H, m), 0.45-0.55 (2H, m),1.32 (1H, m), 1.88-1.93 (2H, m), 2.64 (2H, t, J=7.3 Hz), 2.78-2.88 (2H,m) 3.90 (3H, s), 4.00 (2H, d, J=7.3 Hz), 7.28 (1H, dd, J=8.5, 8.5 Hz),7.70-7.78 (2H, m), 7.96 (1H, s).

[1796] IR (KBr) cm⁻¹: 3437, 1648, 1608, 1526, 1273, 1122, 1021, 762.Referential Example Preparation of 3-(2,6-dichlorophenyl)-1-propanolmethanesulfonate

[1797] 1) Preparation of ethyl 2,6-dichlorocinnamate

[1798] To a solution of 2,6-dichlorobenzaldehyde (350 mg, 2.0 mmol) andtriethyl phosphonoacetate (448 mg, 2.6 mmol) in THF (5 mL), potassiumtert-butoxide (291 mg, 2.6 mmol) was added under ice cooling, and at thesame temperature, the mixture was stirred for 2 hours. A saturatedaqueous solution of ammonium chloride was added to the reaction mixture,followed by extraction with ethyl acetate. The organic layer was driedover anhydrous sodium sulfate and then concentrated under reducedpressure. Further, the residue was purified by chromatography on asilica gel column (hexane/ethyl acetate=50/1) to yield the titlecompound as a colorless syrupy substance (yield: 65.1%).

[1799]¹H NMR (400 MHz, CDCl₃) δ: 1.35 (3H, t, J=7.2 Hz), 4.30 (2H, q,J=7.2 Hz), 6.59 (1H, d, J=16.4 Hz), 7.19 (1H, t, J=8.0 Hz), 7.36 (2H, t,J=8.0 Hz), 7.79 (1H, d, J=16.4 Hz).

[1800] 2) Preparation of 3-(2,6-dichlorophenyl)-1-propanol Lithiumaluminum hydride (98.8 mg, 2.60 mmol) was added to THF (5 mL), and underice-cold strring, a solution of ethyl 2,6-dichlorocinnamate (319 mg,1.30 mmol) in THF (5 mL) was added dropwise. The mixture was thenstirred at room temperature for 30 minutes. A small amount of asaturated aqueous solution of ammonium chloride was added to thereaction mixture, followed by drying over anhydrous magnesium sulfate.Subsequent to filtration through Celite, the mixture was concentratedunder reduced pressure and further, purified by chromatography on asilica gel column (hexane/ethyl acetate=10/1) to yield the titlecompound as a pale yellow syrupy substance (yield: 46.9%).

[1801]¹H NMR (400 MHz, CDCl₃) δ: 1.83-1.93 (2H, m), 3.02 (2H, t, J=7.8Hz), 3.73 (2H, t, J=6.3 Hz), 7.09 (1H, t, J=8.3 Hz), 7.27 (2H, d, J=8.3Hz).

[1802] 3) Preparation of 3-(2,6-dichlorophenyl)-1-propanolmethanesulfonate

[1803] To a solution of 3-(2,6-dichlorophenyl)-1-propanol (125 mg, 0.61mmol) and triethylamine (123 mg, 1.22 mmol) in methylene chloride (3mL), methanesulfonyl chloride (105 mg, 0.915 mmol) was added under icecooling, followed by stirring at room temperature for 2 hours. Brine wasadded to the reaction mixture. The organic layer was allowed toseparate, was collected, and was then dried over anhydrous sodiumsulfate. Subsequent to concentration under reduced pressure, the residuewas purified by chromatography on a silica gel column (hexane/ethylacetate=10/1) to yield the title compound as a pale yellow syrupysubstance (yield: quantitative).

[1804]¹H NMR (400 MHz, CDCl₃) δ: 2.02-2.12 (2H, m), 3.00-3.10 (5H, m),4.32 (2H, t, J=6.3 Hz), 7.10 (1H, t, J=8.3 Hz), 7.28 (2H, d, J=8.3 Hz).

Example 218

[1805] Preparation of2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-o ne

[1806] 1) Preparation of4-carboxy-2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1807] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(4-chlorophenyl)-1-propanol methanesulfonate were reacted. Withoutpurification, the reaction product was reacted further following theprocedure of Example 1 (7) to yield the title compound as a yellowcrystalline powder (yield: 80.8%).

[1808] Melting point: 120-123° C.

[1809]¹H NMR (400 MHz, CDCl₃) δ: 2.22-2.32 (2H, m), 2.37 (3H, d, J=1.7Hz), 2.74 (2H, t, J=7.3 Hz), 4.06 (2H, t, J=7.3 Hz), 7.13 (2H, d, J=8.5Hz), 7.14 (1H, m), 7.24 (2H, d, J=8.5 Hz), 7.60-7.70 (2H, m), 8.59 (1H,s).

[1810] 2) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1811] Following the procedure of Example 1 (8),4-carboxy-2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as ayellow oil (yield: 25.2%).

[1812]¹H NMR (400 MHz, CDCl₃) δ: 2.16-2.24 (2H, m), 2.35 (3H, d, J=1.7Hz), 2.70 (2H, t, J=7.3 Hz), 4.28 (2H, t, J=7.3 Hz), 4.69 (2H, d, J=1.2Hz), 7.09 (1H, m), 7.14 (2H, d, J=8.3 Hz), 7.23 (2H, d, J=8.3 Hz),7.55-7.64 (2H, m), 7.64 (1H, s).

[1813] 3) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1814] Following the procedure of Example 1 (9),2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 89.8%).

[1815]¹H NMR (400 MHz, CDCl₃) δ: 2.16-2.24 (2H, m), 2.36 (3H, d, J=2.0Hz), 2.71 (2H, t, J=7.3 Hz), 3.17 (3H, s), 4.28 (2H, t, J=7.3 Hz), 5.25(2H, d, J=1.5 Hz), 7.10 (1H, m), 7.13 (2H, d, J=8.5 Hz), 7.23 (2H, d,J=8.5 Hz), 7.55-7.66 (2H, m), 7.73 (1H, t, J=1.2 Hz).

[1816] 4) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1817] Following the procedure of Example 1 (10),2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 59.2%).

[1818]¹H NMR (400 MHz, CDCl₃) δ: 2.16-2.23 (2H, m), 2.36 (3H, s), 2.37(3H, d, J=1.7 Hz), 2.55-2.73 (10H, m), 3.56 (2H, d, J=1.5 Hz), 4.27 (2H,t, J=7.3 Hz), 7.10 (1H, m), 7.14 (2H, d, J=8.5 Hz), 7.21 (2H, d, J=8.5Hz), 7.55-7.65 (2H, m), 7.69 (1H, s).

[1819] IR (Neat) cm⁻¹: 1652, 1608, 1493, 1239, 1015, 755.

[1820] Mass m/z: 468 (M⁺), 470 (M⁺)

Example 219

[1821] Preparation of2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-o ne

[1822] 1) Preparation of4-carboxy-2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1823] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(2-chlorophenyl)-1-propanol methanesulfonate were reacted. Withoutpurification, the reaction product was reacted further following theprocedure of Example 1 (7) to yield the title compound as a yellowcrystalline powder (yield: 76.8%).

[1824] Melting point: 156-159° C.

[1825]¹H NMR (400 MHz, CDCl₃) δ: 2.27-2.35 (2H, m), 2.37 (3H, d, J=2.0Hz), 2.88 (2H, t, J=7.3 Hz), 4.45 (2H, t, J=7.3 Hz), 7.11-7.34 (5H, m),7.63-7.72 (2H, m) 8.60 (1H, s).

[1826] 2) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1827] Following the procedure of Example 1 (8),4-carboxy-2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as ayellow oil (yield: 38.9%).

[1828]¹H NMR (400 MHz, CDCl₃) δ: 2.20-2.27 (2H, m), 2.35 (3H, d, J=2.0Hz), 2.85 (2H, t, J=7.3 Hz), 4.33 (2H, t, J=7.3 Hz), 4.71 (2H, d, J=1.2Hz), 7.06-7.34 (5H, m), 7.56-7.64 (2H, m), 7.65 (1H, s).

[1829] 3) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1830] Following the procedure of Example 1 (9),2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a brown oil (yield: 92.5%).

[1831]¹H NMR (400 MHz, CDCl₃) δ: 2.20-2.27 (2H, m), 2.36 (3H, d, J=1.7Hz), 2.85 (2H, t, J=7.1 Hz), 3.17 (3H, s), 4.33 (2H, t, J=7.1 Hz), 5.27(2H, d, J=1.2 Hz), 7.07-7.34 (5H, m), 7.56-7.65 (2H, m), 7.75 (1H, s).

[1832] 4) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1833] Following the procedure of Example 1 (10),2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 66.7%).

[1834]¹H NMR (400 MHz, CDCl₃) δ: 2.17-2.26 (2H, m), 2.34 (3H, s), 2.36(3H, d, J=2.0 Hz), 2.50-2.68 (8H, m), 2.85 (2H, t, J=7.6 Hz), 3.58 (2H,d, J=1.5 Hz), 4.32 (2H, t, J=7.3 Hz), 7.07-7.35 (5H, m), 7.58 (1H, m),7.65 (1H, m), 7.72 (1H, s).

[1835] IR (Neat) cm⁻¹: 1652, 1608, 1456, 1238, 1015, 753.

[1836] Mass m/z: 468 (M⁺), 470 (M⁺).

Example 220

[1837] Preparation of2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-o ne dihydrochloride

[1838] Following the procedure of Example 4,2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as colorless flakes (yield:62.0%).

[1839] Melting point: 230-236° C.

[1840]¹H NMR (400 MHz, DMSO-d₆) δ: 2.08-2.16 (2H, m), 2.32 (3H, s), 2.79(2H, t, J=7.6 Hz), 2.81 (3H, s), 3.20-3.63 (10H, m), 4.23 (2H, t, J=7.6Hz), 7.20-7.32 (3H, m), 7.38-7.39 (2H, m), 7.41 (1H, s), 7.71 (1H, m),8.27 (1H, brs).

[1841] IR (KBr) cm⁻¹: 3301, 2984, 1651, 1608.

Example 221

[1842] Preparation of2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-o ne

[1843] 1) Preparation of4-carboxy-2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1844] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(3-chlorophenyl)-1-propanol methanesulfonate were reacted. Withoutpurification, the reaction product was reacted further following theprocedure of Example 1 (7) to yield the title compound as a yellowcrystalline powder (yield: 79.1%).

[1845] Melting point: 117-120° C.

[1846]¹H NMR (400 MHz, CDCl₃) δ: 2.26-2.33 (2H, m), 2.37 (3H, d, J=2.0Hz), 2.75 (2H, t, J=7.3 Hz), 4.42 (2H, t, J=7.3 Hz), 7.06-7.22 (5H, m),7.63-7.70 (2H, m) 8.58 (1H, s).

[1847] 2) Preparation of2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1848] Following the procedure of Example 1 (8),4-carboxy-2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as ayellow oil (yield: 51.8%).

[1849]¹H NMR (400 MHz, CDCl₃) δ: 2.18-2.26 (2H, m), 2.36 (3H, d, J=2.0Hz), 2.72 (2H, t, J=7.6 Hz), 4.30 (2H, t, J=7.3 Hz), 4.70 (2H, s),7.07-7.22 (5H, m) 7.55-7.63 (2H, m), 7.64 (1H, s).

[1850] 3) Preparation of2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1851] Following the procedure of Example 1 (9),2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a brown oil (yield: 86.7%).

[1852]¹H NMR (400 MHz, CDCl₃) δ: 2.20-2.26 (2H, m), 2.36 (3H, d, J=1.7Hz), 2.71 (2H, t, J=7.6 Hz), 3.17 (3H, s), 4.30 (2H, t, J=7.1 Hz), 5.25(2H, d, J=1.2 Hz), 7.07-7.22 (5H, m), 7.55-7.64 (2H, m), 7.73 (1H, s).

[1853] 4) Preparation of2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1854] Following the procedure of Example 1 (10),2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 56.2%).

[1855]¹H NMR (400 MHz, CDCl₃) δ: 2.17-2.25 (2H, m), 2.36 (3H, s), 2.37(3H, s), 2.55-2.68 (8H, m), 2.71 (2H, t, J=7.6 Hz), 3.57 (2H, d, J=1.2Hz), 4.28 (2H, t, J=7.3 Hz), 7.07-7.22 (5H, m), 7.57 (1H, m), 7.64 (1H,m), 7.70 (1H, s).

[1856] IR (Neat) cm⁻¹: 1652, 1607, 1456, 1239, 1015, 755.

[1857] Mass m/z: 468 (M⁺), 470 (M⁺)

Example 222

[1858] Preparation of2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1859] 1) Preparation of4-carboxy-2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1860] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and4-chlorobenzyl chloride were reacted. Without purification, the reactionproduct was reacted further following the procedure of Example 1 (7) toyield the title compound as a pale yellow crystalline powder (yield:46.5%).

[1861] Melting point: 219.5-220.5° C.

[1862]¹H NMR (400 MHz, CDCl₃) δ: 2.37 (3H, d, J=1.7 Hz), 5.48 (2H, s),7.14 (1H, dd, J=8.8, 8.8 Hz), 7.35 (2H, d, J=8.3 Hz), 7.46 (2H, d, J=8.3Hz), 7.63-7.70 (2H, m), 8.62 (1H, s), 13.90 (1H, brs).

[1863] IR (KBr) cm⁻¹: 1745, 1634, 1561, 1493, 1475, 1245, 806.

[1864] 2) Preparation of2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1865] Following the procedure of Example 1 (8),4-carboxy-2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as slightly yellow needles(yield: 23.3%).

[1866] Melting point: 157.1-158.3° C.

[1867]¹H NMR (400 MHz, CDCl₃) δ: 2.35 (3H, d, J=2.0 Hz), 4.70 (2H, s),5.36 (2H, s), 7.09 (1H, dd, J=8.8, 8.8 Hz), 7.31 (2H, d, J=8.3 Hz), 7.42(2H, d, J=8.3 Hz), 7.56-7.65 (2H, m), 7.67 (1H, s).

[1868] IR (KBr) cm⁻¹: 3422, 1645, 1604, 1508, 1459, 1239, 1091, 819.

[1869] Mass m/z: 358 (M⁺), 360 (M⁺)

[1870] 3) Preparation of2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1871] Following the procedure of Example 1 (9),2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as paleyellow needles (yield: 89.1%).

[1872] Melting point: 131.8-132.7° C.

[1873]¹H NMR (400 MHz, CDCl₃) δ: 2.36 (3H, d, J=2.0 Hz), 3.15 (3H, s),5.25 (2H, d, J=1.5 Hz) 5.36 (2H, s), 7.10 (1H, dd, J=9.0, 9.0 Hz), 7.31(2H, d, J=8.3 Hz), 7.42 (2H, d, J=8.3 Hz), 7.55-7.63 (2H, m), 7.76 (1H,s).

[1874] IR (KBr) cm⁻¹: 1661, 1618, 1352, 1165, 877.

[1875] Mass m/z: 436 (M⁺), 438 (M⁺).

[1876] 4) Preparation of2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1877] Following the procedure of Example 1 (10),2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the titlecompound as pale yellow needles (yield: 58.7%).

[1878] Melting point: 133.3-133.8° C.

[1879]¹H NMR (400 MHz, CDCl₃) δ: 2.35 (3H, d, J=2.0 Hz), 2.43 (3H, s),2.70 (8H, brs), 3.58 (2H, d, J=1.2 Hz), 5.35 (2H, s), 7.10 (1H, dd,J=8.8, 8.8 Hz), 7.30 (2H, d, J=8.3 Hz), 7.43 (2H, d, J=8.3 Hz), 7.59(1H, m), 7.62 (1H, dd, J=7.3, 2.0 Hz), 7.71 (1H, s).

[1880] IR (KBr) cm⁻¹: 2798, 1655, 1606, 1492, 1235, 1166, 1104.

[1881] Mass m/z: 440 (M⁺), 442 (M⁺)

Example 223

[1882] Preparation of2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[1883] Following the procedure of Example 4,2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 88.5%).

[1884] Melting point: 246.4-249.7° C. (dec.)

[1885]¹H NMR (400 MHz, DMSO-d₆) δ: 2.31 (3H, s), 2.82 (3H, s), 3.17 (8H,brs), 4.09 (2H, brs), 5.36 (2H, s), 7.30 (1H, dd, J=9.0, 9.0 Hz), 7.42(4H, s), 7.76 (1H, m), 7.84 (1H, dd, J=7.3, 2.2 Hz), 8.34 (1H, s).

[1886] IR (KBr) cm⁻¹: 1654, 1612, 1505.

[1887] Mass m/z: 440 (M⁺), 442 (M⁺)

Example 224

[1888] Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1889] 1) Preparation of4-carboxy-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1890] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and2-chlorobenzyl chloride were reacted. Without purification, the reactionproduct was reacted further following the procedure of Example 1 (7) toyield the title compound as pale yellow needles (yield: 76.4%).

[1891] Melting point: 185.1-185.9° C.

[1892]¹H NMR (400 MHz, CDCl₃) δ: 2.34 (3H, s), 5.67 (2H, s), 7.10 (1H,dd, J=8.8, 8.8 Hz), 7.25-7.35 (3H, m), 7.46 (1H, m), 7.62 (1H, m), 7.65(1H, d, J=7.3 Hz), 8.66 (1H, s), 13.92 (1H, s).

[1893] IR (KBr) cm⁻¹: 1751, 1638, 1565, 1472, 1239.

[1894] Mass m/z: 372 (M⁺), 374 (M⁺)

[1895] 2) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1896] Following the procedure of Example 1 (8),4-carboxy-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:21.3%).

[1897] Melting point: 149.0-149.7° C.

[1898]¹H NMR (400 MHz, CDCl₃) δ: 2.32 (3H, d, J=1.7 Hz), 4.73 (2H, d,J=1.2 Hz), 5.55 (2H, s), 7.06 (1H, dd, J=8.8, 8.8 Hz), 7.15-7.26 (3H,m), 7.40 (1H, m), 7.57 (1H, m), 7.62 (1H, dd, J=7.3, 2.2 Hz), 7.73 (1H,t, J=1.2 Hz).

[1899] IR (KBr) cm⁻¹: 3409, 1668, 1652, 1506, 1446, 1241.

[1900] Mass m/z: 358 (M⁺), 360 (M⁺).

[1901] 3) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1902] Following the procedure of Example 1 (9),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound asslightly yellow needles (yield: 82.1%).

[1903] Melting point: 142.3-143.0° C.

[1904]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, d, J=1.7 Hz), 3.16 (3H, s),5.29 (2H, d, J=1.2 Hz), 5.56 (2H, s), 7.07 (1H, dd, J=8.8, 8.8 Hz),7.19-7.28 (3H, m) 7.42 (1H, m), 7.56 (1H, m), 7.60 (1H, dd, J=7.3, 2.2Hz), 7.81 (1H, s).

[1905] IR (KBr) cm⁻¹: 1659, 1618, 1613, 1355, 1166, 1034.

[1906] Mass m/z: 436 (M⁺), 438 (M⁺).

[1907] 4) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1908] Following the procedure of Example 1 (10),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the titlecompound as pale yellow needles (yield: 53.4%).

[1909] Melting point: 149.7-150.9° C.

[1910]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, d, J=1.7 Hz), 2.38 (3H, s),2.61 (4H, brs), 2.68 (4H, brs), 3.61 (2H, d, J=1.5 Hz), 5.55 (2H, s),7.06 (1H, dd, J=8.8, 8.8 Hz), 7.17-7.26 (3H, m), 7.41 (1H, m), 7.56 (1H,m), 7.62 (1H, dd, J=7.1, 2.0 Hz), 7.77 (1H, s).

[1911] IR (KBr) cm⁻¹: 2792, 1659, 1618, 1611, 1504, 1285, 1237, 1170.

[1912] Mass m/z: 440 (M⁺), 442 (M⁺).

Example 225

[1913] Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one dihydrochloride

[1914] Following the procedure of Example 4,2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly yellow crystallinepowder (yield: 78.1%).

[1915] Melting point: 191-202° C. (dec.)

[1916]¹H NMR (400 MHz, CD₃OD) δ: 2.31 (3H, d, J=1.7 Hz), 3.01 (3H, s),3.68 (8H, brs), 4.40 (2H, s), 5.57 (2H, s), 7.12 (1H, dd, J=8.8, 8.8Hz), 7.27-7.35 (3H, m), 7.46 (1H, m), 7.72 (1H, m), 7.77 (1H, d, J=7.1Hz), 8.40 (1H, s).

[1917] IR (KBr) cm⁻¹: 1656, 1612, 1504, 1446, 1128.

[1918] Mass m/z: 440 (M⁺), 442 (M⁺).

Example 226

[1919] Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one

[1920] 1) Preparation of4-bromomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1921] Following the procedure of Example 211 (1),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound asslightly yellow needles (yield: 46.2%).

[1922] Melting point: 113-115° C.

[1923]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, d, J=2.0 Hz), 4.50 (2H, d,J=0.98 Hz), 5.75 (2H, s), 7.07 (1H, dd, J=8.8, 8.8 Hz), 7.21-7.25 (3H,m), 7.42 (1H, m) 7.51-7.61 (2H, m), 7.83 (1H, t, J=0.98 Hz).

[1924] 2) Preparation of2-(2-chlorobenzyl)-4-[2,2-di(tert-butoxycarbony)ethyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1925] Following the procedure of Example 211 (2),4-bromomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow oil (yield: 88.4%).

[1926]¹H NMR (400 MHz, CDCl₃) δ: 1.41 (18H, s), 2.31 (3H, d, J=1.7 Hz),3.14 (2H, d, J=7.8 Hz), 3.87 (1H, t, J=7.8 Hz), 5.54 (2H, s), 7.04 (1H,dd, J=8.8, 8.8 Hz), 7.14-7.24 (3H, m), 7.40 (1H, m), 7.48-7.56 (2H, m),7.57 (1H, s).

[1927] 3) Preparation of4-(2-carboxyethyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1928] Following the procedure of Example 211 (3),2-(2-chlorobenzyl)-4-[2,2-di(tert-butoxycarbonyl)ethyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow powder (yield:99.1%).

[1929]¹H NMR (400 MHz, CDCl₃) δ: 2.31 (3H, d, J=1.7 Hz), 2.81 (2H, t,J=6.8 Hz), 2.98 (2H, t, J=6.8 Hz), 5.55 (2H, s), 7.05 (1H, dd, J=9.0,9.0 Hz), 7.16-7.25 (3H, m), 7.41 (1H, m), 7.50-7.57 (2H, m), 7.59 (1H,s).

[1930] 4) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-one

[1931] Following the procedure of Example 1 (8),4-(2-carboxyethyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as apale yellow oil (yield: 77.2%).

[1932]¹H NMR (400 MHz, CDCl₃) δ: 1.88-1.95 (2H, m), 2.32 (3H, d, J=1.5Hz), 2.82 (2H, t, J=7.1 Hz), 3.63 (2H, t, J=6.8 Hz), 5.56 (2H, s), 7.05(1H, dd, J=8.8, 8.8 Hz), 7.25-7.28 (3H, m), 7.41 (1H, m), 7.55-7.60 (2H,m), 7.56 (1H, s).

[1933] 5) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one

[1934] Following the procedure of Example 1 (9),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-one was reacted to yield the title compound as ayellow oil (yield: 97.0%).

[1935]¹H NMR (400 MHz, CDCl₃) δ: 2.14-2.21 (2H, m), 2.32 (3H, d, J=1.7Hz), 2.81 (2H, t, J=7.1 Hz), 3.02 (3H, s), 4.30 (2H, t, J=6.1 Hz), 5.54(2H, s), 7.05 (1H, dd, J=8.8, 8.8 Hz), 7.17-7.25 (3H, m), 7.41 (1H, m)7.53-7.62 (2H, m), 7.58 (1H, s).

[1936] 6) Preparation of2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one

[1937] Following the procedure of Example 1 (9),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one was reacted to yield the titlecompound as a yellow oil (yield: 75.9%).

[1938]¹H NMR (400 MHz, CDCl₃) δ: 1.84-1.95 (2H, m), 2.32 (3H, brs), 2.33(3H, s), 2.45-2.58 (8H, m), 2.70 (2H, t, J=7.8 Hz), 3.26 (2H, t, J=4.9Hz), 5.54 (2H, s), 7.05 (1H, dd, J=8.8, 8.8 Hz), 7.15-7.23 (3H, m), 7.40(1H, m), 7.51 (1H, s), 7.53-7.59 (2H, m).

[1939] IR (Neat) cm⁻¹: 1655, 1608, 1447, 1239, 1014, 754.

[1940] Mass m/z: 468 (M⁺), 470 (M⁺).

Example 227

[1941] Preparation of4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1942] Following the procedure of Example 24 (1),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one was reacted. Without purification,the reaction product was reacted further following the procedure ofExample 24 (2) to yield the title compound as a slightly yellowcrystalline powder (yield: 43.9%).

[1943] Melting point: 80-85° C.

[1944]¹H NMR (400 MHz, CDCl₃) δ: 1.85-1.95 (2H, m), 2.31 (3H, d, J=1.7Hz), 2.74 (2H, t, J=7.8 Hz), 2.85 (2H, t, J=6.8 Hz), 5.54 (2H, s), 7.04(1H, dd, J=8.8, 8.8 Hz), 7.15-7.24 (3H, m), 7.40 (1H, m), 7.56 (1H, s),7.58-7.59 (2H, m).

[1945] IR (KBr) cm⁻¹: 3425, 1652, 1607, 1445, 1238, 1039, 749.

[1946] Mass m/z: 385 (M⁺), 387 (M⁺)

Example 228

[1947] Preparation of4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one hydrochloride

[1948] Following the procedure of Example 4,4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as apale-brown crystalline powder (yield: 55.9%).

[1949] Melting point: 161-165° C.

[1950]¹H NMR (400 MHz, CD₃OD) δ: 1.98-2.06 (2H, m), 2.30 (3H, brs), 2.77(2H, t, J=7.8 Hz), 3.00 (2H, t, J=7.6 Hz), 5.56 (2H, s), 7.10 (1H, dd,J=9.0, 9.0 Hz), 7.19 (1H, m), 7.24-7.33 (2H, m), 7.45 (1H, m), 7.67 (1H,m), 7.72 (1H, m), 7.94 (1H, s).

[1951] IR (KBr) cm⁻¹: 3435, 1644, 1602, 1445, 1240, 1040, 748.

Example 229

[1952] Preparation of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-on e

[1953] 1) Preparation of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one

[1954] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and2-(2-chlorophenyl)ethanol methanesulfonate were reacted to yield thetitle compound as a pale yellow solid (yield: 59.8%).

[1955]¹H NMR (400 MHz, CDCl₃) δ: 2.32 (3H, s), 3.33 (2H, t, J=7.3 Hz),3.99 (3H, s), 4.58 (2H, t, J=7.3 Hz), 7.05 (1H, dd, J=8.8, 8.8 Hz),7.14-7.27 (3H, m) 7.34-7.44 (3H, m), 8.19 (1H, s).

[1956] 2) Preparation of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1957] To a solution of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one (480 mg, 1.20 mmol) in THF/methanol (2mL/1 mL), cerium (III) chloride hexahydrate (425 mg, 1.20 mmol) wasadded at −15° C., followed by the addition of sodium borohydride (45 mg,1.20 mmol). After stirred for 10 minutes, a saturated aqueous solutionof ammonium chloride was added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The extract was dried over anhydroussodium sulfate, concentrated under reduced pressure, and then, purifiedby chromatography on a silica gel (hexane/ethyl acetate=2/1) to yieldthe title compound as a pale-yellow, syrupy sustance (yield: 11.0%).

[1958]¹H NMR (400 MHz, CDCl₃) δ: 2.32 (3H, d, J=2.0 Hz), 3.32 (2H, t,J=7.2 Hz), 4.54 (2H, t, J=7.2 Hz), 4.69 (2H, s), 7.05 (1H, dd, J=9.2,9.2 Hz), 7.13-7.23 (3H, m), 7.36 (1H, m), 7.42-7.48 (2H, m), 7.62 (1H,d, J=1.0 Hz).

[1959] 3) Preparation of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1960] Following the procedure of Example 1 (9),2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compoundas a pale yellow syrup (yield: 86.1%).

[1961]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, d, J=1.8 Hz), 3.16 (3H, s),3.31 (2H, t, J=7.2 Hz), 4.55 (2H, t, J=7.2 Hz), 5.26 (2H, d, J=1.4 Hz),7.06 (1H, dd, J=9.2, 9.2 Hz), 7.14-7.21 (3H, m), 7.37 (1H, m), 7.40-7.47(2H, m), 7.72 (1H, t, J=1.8 Hz).

[1962] 4) Preparation of2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1963] Following the procedure of Example 1 (10),2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield thetitle compound as a pale yellow syrup (yield: 61.2%).

[1964]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (6H, s), 2.46-2.67 (8H, m), 3.31(2H, t, J=7.3 Hz), 3.57 (2H, d, J=1.2 Hz), 4.53 (2H, t, J=7.3 Hz), 7.05(1H, dd, J=9.3, 9.3 Hz), 7.13-7.24 (3H, m), 7.36 (1H, m), 7.42-7.47 (2H,m), 7.70 (1H, s).

[1965] IR (Neat) cm⁻¹: 1653, 1606, 1504, 1284, 1238, 1116.

Example 230

[1966] Preparation of2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-on e

[1967] 1) Preparation of4-carboxy-2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1968] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and2-(4-chlorophenyl)ethanol methanesulfonate were reacted. Withoutpurification, the reaction product was reacted further following theprocedure of Example 1 (7) to yield the title compound as a pale yellowsolid (yield: 56.3%).

[1969]¹H NMR (400 MHz, CDCl₃) δ: 2.36 (3H, d, J=1.8 Hz), 3.20 (2H, t,J=7.4 Hz), 4.60 (2H, t, J=7.4 Hz), 7.11 (1H, dd, J=8.2, 8.2 Hz), 7.17(2H, d, J=8.4 Hz), 7.22-7.31 (2H, m), 7.49-7.55 (2H, m), 8.59 (1H, s).

[1970] 2) Preparation of2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1971] Following the procedure of Example 1 (8),4-carboxy-2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as apale yellow oil (yield: 37.2%).

[1972]¹H NMR (400 MHz, CDCl₃) δ: 2.34 (3H, d, J=2.0 Hz), 3.14 (2H, t,J=7.4 Hz), 4.47 (2H, t, J=7.4 Hz), 4.70 (2H, s), 7.07 (1H, dd, J=9.2,9.2 Hz), 7.18 (2H, d, J=8.4 Hz), 7.26 (2H, d, J=8.4 Hz), 7.45-7.51 (2H,m) 7.63 (1H, t, J=1.2 Hz).

[1973] 3) Preparation of2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1974] Following the procedure of Example 1 (9),2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compoundas a yellow solid (yield: 34.0%).

[1975]¹H NMR (400 MHz, CDCl₃) δ: 2.35 (3H, d, J=1.9 Hz), 3.11-3.17 (5H,m), 4.48 (2H, t, J=7.3 Hz), 5.26 (2H, d, J=1.5 Hz), 7.08 (1H, dd, J=9.3,9.3 Hz), 7.17 (2H, d, J=8.3 Hz), 7.24-7.29 (2H, m), 7.44-7.53 (2H, m)7.73 (1H, t, J=1.2 Hz).

[1976] 4) Preparation of2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1977] Following the procedure of Example 1 (10),2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield thetitle compound as a colorless crystalline powder (yield: 45.2%).

[1978] Melting point: 113-114° C.

[1979]¹H NMR (400 MHz, CDCl₃) δ: 2.32 (3H, s), 2.35 (3H, d, J=2.0 Hz),2.45-2.66 (8H, m), 3.13 (2H, t, J=7.6 Hz), 3.57 (2H, d, J=1.4 Hz), 4.46(2H, t, J=7.6 Hz), 7.08 (1H, dd, J=8.5, 8.5 Hz), 7.18 (2H, d, J=8.3 Hz),7.24-7.28 (2H, m), 7.45-7.50 (2H, m), 7.70 (1H, t, J=1.4 Hz).

[1980] IR (KBr) cm⁻¹: 1654, 1613, 1505, 1285, 1242, 1167, 1123.

Example 231

[1981] Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1982] 1) Preparation of4-carboxymethyl-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1983] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and2,6-dichlorobenzyl bromide were reacted. Without purification, thereaction product was reacted further following the procedure of Example1 (7) to yield the title compound as a pale yellow solid (yield: 90.3%).

[1984]¹H NMR (400 MHz, CDCl₃) δ: 2.28 (3H, d, J=1.8 Hz), 5.81 (2H, s),7.03 (1H, dd, J=8.8, 8.8 Hz), 7.31 (1H, dd, J=8.8, 7.4 Hz), 7.39-7.49(4H, m), 8.62 (1H, s).

[1985] 2) Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[1986] Following the procedure of Example 1 (8),4-carboxy-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow solid (yield:46.1%).

[1987]¹H NMR (400 MHz, CDCl₃) δ: 2.26 (3H, d, J=1.7 Hz), 4.74 (2H, s),5.70 (2H, s), 6.98 (1H, dd, J=9.0, 9.0 Hz), 7.25 (1H, dd, J=8.6, 7.3Hz), 7.32-7.45 (4H, m), 7.66 (1H, s).

[1988] 3) Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[1989] Following the procedure of Example 1 (9),2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as apale yellow solid (yield: 78.9%).

[1990]¹H NMR (400 MHz, CDCl₃) δ: 2.27 (3H, d, J=1.7 Hz), 3.17 (3H, s),5.31 (2H, d, J=1.2 Hz), 5.69 (2H, s), 6.99 (1H, dd, J=8.8, 8.8 Hz), 726(1H, m), 7.34-7.44 (4H, m), 7.75 (1H, t, J=1.4 Hz).

[1991] 4) Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[1992] Following the procedure of Example 1 (10),2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the titlecompound as a colorless crystalline powder (yield: 69.4%).

[1993] Melting point: 150-152° C.

[1994]¹H NMR (400 MHz, CDCl₃) δ: 2.27 (3H, d, J=1.8 Hz), 2.33 (3H, s),2.45-2.67 (8H, m), 3.62 (2H, d, J=1.4 Hz), 5.69 (2H, s), 6.99 (1H, dd,J=9.0, 9.0 Hz), 7.23 (1H, dd, J=8.6, 7.4 Hz), 7.34-7.44 (4H, m), 7.73(1H, s).

[1995] IR (KBr) cm⁻¹: 1658, 1619, 1505, 1437, 1238, 1168.

Example 232

[1996] Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

[1997] 1) Preparation of4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[1998] Following the procedure of Example 1 (10),2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and tert-butyll-piperazinecarboxylate were reacted to yield the title compound as ayellow oil (yield: 90.8%).

[1999]¹H NMR (400 MHz, CDCl₃) δ: 1.47 (9H, s), 2.26 (3H, s), 2.53 (4H,t, J=4.9 Hz), 3.50((4H, t, J=4.9 Hz), 3.61 (2H, s), 5.69 (2H, s), 6.98(1H, dd, J=8.8, 8.8 Hz), 7.23 (1H, dd, J=8.5, 7.3 Hz), 7.35-7.43 (4H,m), 7.75 (1H, s).

[2000] 2) Preparation of2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one

[2001] Following the procedure of Example 20,4-(4-tert-butoxycarbonyl-1-piperazinyl)methyl-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted toyield the title compound as a colorless amorphous powder (yield: 84.6%).

[2002]¹H NMR (400 MHz, CDCl₃) δ: 2.27 (3H, d, J=1.7 Hz), 2.51-2.60 (4H,m), 2.95 (4H, t, J=4.6 Hz), 3.59 (2H, d, J=1.2 Hz), 5.69 (2H, s), 6.99(1H, dd, J=8.8, 8.8 Hz), 7.24 (1H, m), 7.35-7.44 (4H, m), 7.76 (1H, s).

[2003] IR (KBr) cm⁻¹: 1652, 1606, 1504, 1438, 1239, 1119.

Example 233

[2004] Preparation of4-aminomethyl-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[2005] Following the procedure of Example 24 (1),2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted. Without purification,the reaction product was reacted further following the procedure ofExample 24 (2) to yield the title compound as a yellow-brown crystallinepowder (yield: 12.7%).

[2006]¹H NMR (400 MHz, CDCl₃) δ: 2.17 (2H, brs), 2.25 (3H, d, J=2.0 Hz),3.94 (2H, d, J=1.0 Hz) 5.69 (2H, s), 6.97 (1H, dd, J=9.0, 9.0 Hz), 7.24(1H, dd, J=8.5, 7.3 Hz), 7.34-7.45 (4H, m), 7.70 (1H, s).

[2007] IR (KBr) cm⁻¹: 3362, 1643, 1598, 1504, 1438, 1238, 1121.

Example 234

[2008] Preparation of2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[2009] 1) Preparation of4-carboxy-2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[2010] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(2, 6-dichlorophenyl)-1-propanol methanesulfonate were reacted.Without purification, the reaction product was reacted further followingthe procedure of Example 1 (7) to yield the title compound as a paleyellow solid (yield: 89.8%).

[2011]¹H NMR (400 MHz, CDCl₃) δ: 2.22-2.32 (2H, m), 2.37 (3H, d, J=2.0Hz), 3.03-3.08 (2H, m) 4.50 (2H, t, J=7.0 Hz), 7.06-7.17 (2H, m),7.25-7.29 (2H, m), 7.64-7.72 (2H, m), 8.63 (1H, s), 14.12 (1H, s).

[2012] 2) Preparation of2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[2013] Following the procedure of Example 1 (8),4-carboxy-2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compoundas a pale yellow syrup (yield: 31.9%).

[2014]¹H NMR (400 MHz, CDCl₃) δ: 2.14-2.24 (2H, m), 2.35 (3H, d, J=1.8Hz), 3.00-3.06 (2H, m) 4.38 (2H, t, J=7.0 Hz), 4.72 (2H, d, J=1.5 Hz),7.01-7.12 (2H, m), 7.23-7.28 (2H, m), 7.57-7.70 (3H, m).

[2015] 3) Preparation of2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[2016] Following the procedure of Example 1 (9),2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow syrup (yield:25.8%).

[2017]¹H NMR (400 MHz, CDCl₃) δ: 2.14-2.23 (2H, m), 2.36 (3H, d, J=1.8Hz), 2.94-3.05 (2H, m), 3.17 (3H, s), 4.38 (2H, t, J=7.0 Hz), 5.28 (2H,d, J=1.4 Hz), 7.02-7.12 (2H, m), 7.23-7.27 (2H, m), 7.57-7.69 (2H, m),7.76 (1H, t, J=1.4 Hz).

[2018] 4) Preparation of2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-o ne

[2019] Following the procedure of Example 1 (10),2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow syrup (yield:49.7%).

[2020]¹H NMR (400 MHz, CDCl₃) δ: 2.13-2.22 (2H, m), 2.33 (3H, s), 2.36(3H, d, J=1.8 Hz), 2.45-2.67 (8H, m), 2.99-3.05 (2H, m), 3.58 (2H, d,J=1.4 Hz), 4.37 (2H, t, J=7.0 Hz), 7.02-7.12 (2H, m), 7.23-7.40 (2H, m),7.59 (1H, m), 7.65 (1H, m), 7.73 (1H, s).

[2021] IR (Neat) cm⁻¹: 1653, 1607, 1504, 1436, 1238.

Example 235

[2022] Preparation of2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[2023] 1) Preparation of4-carboxy-2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[2024] Following the procedure of Example 1 (6),6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3,4-difluorobenzyl chloride were reacted. Without purification, thereaction product was reacted further following the procedure of Example1 (7) to yield the title compound as a pale yellow solid (yield: 66.7%).

[2025]¹H NMR (400 MHz, CDCl₃) δ: 2.36 (3H, d, J=2.0 Hz), 5.43 (2H, s),7.09-7.20 (2H, m), 7.25 (1H, m), 7.34 (1H, m), 7.60-7.68 (2H, m), 8.61(1H, s).

[2026] 2) Preparation of2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[2027] Following the procedure of Example 1 (8),4-carboxy-2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow solid (yield:40.8%).

[2028]¹H NMR (400 MHz, CDCl₃) δ: 2.33 (3H, d, J=2.0 Hz), 4.69 (2H, d,J=1.2 Hz), 5.31 (2H, s) 6.98-7.17 (2H, m), 7.21 (1H, m), 7.30 (1H, m),7.53-7.62 (2H, m), 7.67 (1H, s).

[2029] 3) Preparation of2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[2030] Following the procedure of Example 1 (9),2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as apale yellow solid (yield: 58.1%).

[2031]¹H NMR (400 MHz, CDCl₃) δ: 2.34 (3H, d, J=1.7 Hz), 3.13 (3H, s),5.24 (2H, d, J=1.2 Hz), 5.31 (2H, s), 7.05-7.15 (2H, m), 7.22 (1H, m),7.30 (1H, m), 7.54-7.62 (2H, m), 7.75 (1H, s).

[2032] 4) Preparation of2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[2033] Following the procedure of Example 1 (10),2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted to yield the titlecompound as a pale-yellow amorphous powder (yield: 70.6%).

[2034]¹H NMR (400 MHz, CDCl₃) δ: 2.32 (3H, s), 2.36 (3H, d, J=1.5 Hz),2.45-2.70 (8H, m), 3.56 (2H, d, J=1.3 Hz), 5.32 (2H, s), 7.07-7.15 (2H,m), 7.23 (1H, m), 7.31 (1H, m), 7.57 (1H, m), 7.63 (1H, m), 7.75 (1H,s).

Example 236

[2035] Preparation of2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[2036] Following the procedure of Example 4,2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield thetitle compound as a colorless crystalline powder (yield: 47.9%).

[2037] Melting point: 220-225° C.

[2038]¹H NMR (400 MHz, DMSO-d₆) δ: 2.31 (3H, s), 2.81 (3H, s), 3.52 (2H,brs), 3.60-4.25 (8H, m) 5.35 (2H, s), 7.25 (1H, m), 7.30 (1H, dd, J=9.3,9.3 Hz), 7.38-7.50 (2H, m), 7.76 (1H, m), 7.84 (1H, d, J=7.3 Hz), 8.27(1H, m).

[2039] IR (KBr) cm⁻¹: 3438, 3011, 2446, 1652, 1605, 1519.

Example 237

[2040] Preparation of4-aminomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one

[2041] Following the procedure of Example 24 (1),2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one was reacted. Without purification, thereaction product was reacted further following the procedure of Example24 (2) to yield the title compound as a pale-yellow crystalline powder(yield: 26.7%).

[2042] Melting point: 97.6-102.2° C.

[2043]¹H NMR (400 MHz, CDCl₃) δ: 2.31 (3H, d, J=1.7 Hz), 3.48 (2H, s),5.55 (2H, s), 7.05 (1H, dd, J=8.8, 8.8 Hz), 7.15-7.25 (3H, m), 7.41 (1H,m), 7.58 (1H, m), 7.62 (1H, dd, J=7.3, 1.7 Hz), 7.76 (1H, s).

[2044] IR (KBr) cm⁻¹: 3404, 1648, 1600, 1505, 1239.

[2045] Mass m/z: 357 (M⁺), 359 (M⁺)

Example 238

[2046] Preparation of4-aminomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one hydrochloride

[2047] Following the procedure of Example 4,4-aminomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as pale yellow needles (yield:68.9%).

[2048] Melting point: 201.9-206.4° C.

[2049]¹H NMR (400 MHz, CD₃OD) δ: 2.31 (3H, d, J=1.7 Hz), 4.17 (2H, s),5.57 (2H, s), 7.12 (1H, dd, J=8.8, 8.8 Hz), 7.25-7.35 (3H, m), 7.46 (1H,m), 7.67 (1H, m), 7.73 (1H, d, J=6.9 Hz), 8.15 (1H, s).

[2050] IR (KBr) cm⁻¹: 3430, 2929, 1652, 1604, 1507, 1476, 1445, 1241.

[2051] Mass m/z: 357 (M⁺), 359 (M⁺).

Example 239

[2052] Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one

[2053] 1) Preparation of4-bromomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-3-methoxyphenyl)-2H-pyridazin-3-one

[2054] Following the procedure of Example 211 (1),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one was reacted to yield the title compound as paleyellow needles (yield: 28.8%).

[2055] Melting point: 120-125° C.

[2056]¹H NMR (400 MHz, CDCl₃) δ: 3.95 (3H, s), 4.46 (2H, s), 5.37 (2H,s), 6.95-7.06 (4H, m), 7.46-7.52 (2H, m), 7.60 (1H, m), 7.77 (1H, s).

[2057] 2) Preparation of4-[2,2-di(tert-butoxycarbony)ethyl]-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[2058] Following the procedure of Example 211 (2),4-bromomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as ayellow oil (yield: 75.1%).

[2059]¹H NMR (400 MHz, CDCl₃) δ: 1.38 (18H, s), 3.10 (2H, d, J=7.6 Hz),3.84 (1H, t, J=7.6 Hz), 3.94 (3H, s), 5.34 (2H, s), 6.98-7.04 (3H, m),7.41-7.50 (4H, m) 7.56 (1H, m).

[2060] 3) Preparation of4-(2-carboxyethyl)-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[2061] Following the procedure of Example 211 (3),4-[2,2-di(tert-butoxycarbonyl)ethyl]-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a slightly yellow powder(yield: 78.8%).

[2062]¹H NMR (400 MHz, CDCl₃) δ: 2.78 (2H, t, J=7.1 Hz), 2.95 (2H, t,J=7.1 Hz), 3.94 (3H, s), 534 (2H, s), 6.99-7.05 (3H, m), 7.44-7.51 (3H,m), 7.52 (1H, s), 7.58 (1H, dd, J=12.4, 2.2 Hz).

[2063] 4) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-one

[2064] Following the procedure of Example 1 (8),4-(2-carboxyethyl)-2-(4-fluorobenzyl)-6-(3-fluoro-4-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as apale yellow powder (yield: 98.0%).

[2065]¹H NMR (400 MHz, CDCl₃) δ: 1.85-1.97 (2H, m), 2.78 (2H, t, J=7.1Hz), 3.61 (2H, t, J=5.9 Hz), 3.95 (3H, s), 5.36 (2H, s), 6.99-7.05 (3H,m), 7.45-7.50 (4H, m), 7.58 (1H, dd, J=12.4, 2.2 Hz).

[2066] 5) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one

[2067] Following the procedure of Example 1 (9),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-hydroxypropyl)-2H-pyridazin-3-one was reacted to yield the title compound as apale-brown crystalline powder (yield: 97.0%).

[2068] Melting point: 101-103° C.

[2069]¹H NMR (400 MHz, CDCl₃) δ: 2.11-2.18 (2H, m), 2.78 (2H, t, J=7.3Hz), 3.02 (3H, s), 3.94 (3H, s), 4.28 (2H, t, J=6.1 Hz), 5.34 (2H, s),7.00-7.04 (3H, m), 7.47-7.50 (3H, m), 7.52 (1H, s), 7.61 (1H, dd,J=12.4, 2.2 Hz)

[2070] 6) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one

[2071] Following the procedure of Example 1 (9),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one was reacted to yield the titlecompound as a pale brown powder (yield: 29.8%).

[2072] Melting point: 108-109° C.

[2073]¹H NMR (400 MHz, CDCl₃) δ: 1.84-1.90 (2H, m), 2.32 (3H, s), 2.45(2H, t, J=7.1 Hz), 2.48-2.60 (8H, m), 2.66 (2H, t, J=7.3 Hz), 3.94 (3H,s), 5.33 (2H, s), 6.98-7.05 (3H, m), 7.44 (1H, s), 7.45-7.51 (3H, m),7.58 (1H, dd, J=12.4, 2.2 Hz).

[2074] IR (KBr) cm⁻¹: 1645, 1601, 1438, 1220, 1016, 807.

[2075] Mass m/z: 468 (M⁺).

Example 240

[2076] Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one

[2077] 1) Preparation of4-[3-(4-tert-butoxycarbonyl-1-piperazinyl)propyl]-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[2078] Following the procedure of Example 1 (10),2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(3-methanesulfonyloxypropyl)-2H-pyridazin-3-one and tert-butyl1-piperazinecarboxylate were reacted to yield the title compound as abrown oil (yield: 37.4%).

[2079]¹H NMR (400 MHz, CDCl₃) δ: 1.46 (9H, s), 1.80-2.00 (2H, m),2.30-2.60 (8H, m), 2.67 (2H, t, J=7.1 Hz), 3.40-3.52 (2H, m), 3.94 (3H,s), 5.33 (2H, s), 6.99-7.05 (3H, m), 7.45-7.51 (4H, m), 7.59 (1H, dd,J=12.4, 2.0 Hz).

[2080] 2) Preparation of2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one

[2081] Following the procedure of Example 20,4-[3-(4-tert-butoxycarbonyl-1-piperazinyl)propyl]-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one was reacted toyield the title compound as a brown oil (yield: 100%).

[2082]¹H NMR (400 MHz, CDCl₃) δ: 1.80-1.91 (2H, m), 2.37-2.51 (6H, m),2.66 (2H, t, J=7.6 Hz), 2.89-2.95 (4H, m), 3.94 (3H, s), 5.34 (2H, s),6.98-7.05 (3H, m), 7.44 (1H, s), 7.45-7.51 (3H, m), 7.58 (1H, dd,J=11.5, 2.2 Hz).

[2083] IR (Neat) cm⁻¹: 1651, 1608, 1438, 1222, 1025, 757.

[2084] Mass m/z: 454 (M⁺).

Example 241

[2085] Preparation of2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[2086] 1) Preparation of4-carboxy-2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-3-methoxyphenyl)-2H-pyridazin-3-one

[2087] Following the procedure of Example 1 (6),6-(3-fluoro-3-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(2-chlorophenyl)-1-propanol methanesulfonate were reacted. Withoutpurification, the reaction product was reacted further following theprocedure of Example 1 (7) to yield the title compound as a pale yellowsolid (yield: 56.0%).

[2088]¹H NMR (400 MHz, CDCl₃) δ: 2.25-2.38 (2H, m), 2.86 (2H, t, J=7.8Hz), 3.95 (3H, s), 4.42 (2H, t, J=7.8 Hz), 7.04 (1H, dd, J=8.5, 8.5 Hz),7.09-7.19 (2H, m), 7.23 (1H, m), 7.30 (1H, m), 7.54 (1H, m), 7.65 (1H,dd, J=12.2, 2.4 Hz), 8.56 (1H, s).

[2089] 2) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[2090] Following the procedure of Example 1 (8),4-carboxy-2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-3-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as apale yellow solid (yield: 32.5%).

[2091]¹H NMR (400 MHz, CDCl₃) δ: 2.17-2.28 (2H, m), 2.84 (2H, t, J=7.6Hz), 3.94 (3H, s), 4.31 (2H, t, J=7.0 Hz), 4.71 (2H, d, J=0.8 Hz), 7.01(1H, dd, J=8.6, 8.6 Hz), 7.13 (1H, ddd, J=7.6, 7.6, 2.0 Hz), 7.18 (1H,ddd, J=7.4, 7.4, 1.4 Hz), 7.26 (1H, dd, J=7.4, 1.7 Hz), 7.32 (1H, dd,J=7.6, 1.4 Hz), 7.51 (1H, ddd, J=8.6, 2.1, 1.2 Hz), 7.61 (1H, dd,J=12.3, 2.2 Hz), 7.66 (1H, s).

[2092] 3) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[2093] Following the procedure of Example 1 (9),2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a yellow solid (yield:79.3%).

[2094]¹H NMR (400 MHz, CDCl₃) δ: 2.18-2.28 (2H, m), 2.85 (2H, t, J=7.6Hz), 3.17 (3H, s), 3.95 (3H, s), 4.32 (2H, t, J=7.3 Hz), 5.27 (2H, d,J=1.2 Hz), 7.03 (1H, dd, J=8.5, 8.5 Hz), 7.13 (1H, ddd, J=7.6, 7.6, 2.0Hz), 7.18 (1H, ddd, J=7.3, 7.3, 1.4 Hz), 7.26 (1H, m), 7.32 (1H, dd,J=7.6, 1.4 Hz), 7.50 (1H, ddd, J=8.6, 2.2, 1.2 Hz), 7.62 (1H, dd,J=12.2, 2.2 Hz), 7.74 (1H, t, J=1.2 Hz).

[2095] 4) Preparation of2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[2096] Following the procedure of Example 1 (10),2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow syrup (yield:76.7%).

[2097]¹H NMR (400 MHz, CDCl₃) δ: 2.17-2.26 (2H, m), 2.33 (3H, s),2.46-2.68 (8H, m), 2.84 (2H, t, J=7.6 Hz), 3.57 (2H, d, J=1.5 Hz), 3.95(3H, s), 4.31 (2H, t, J=7.1 Hz), 7.04 (1H, dd, J=8.6, 8.6 Hz), 7.12 (1H,ddd, J=7.6, 7.6, 1.7 Hz), 7.18 (1H, ddd, J=7.3, 7.3, 1.4 Hz), 7.27 (1H,m), 7.32 (1H, dd, J=7.8, 1.5 Hz), 7.53 (1H, ddd, J=8.6, 2.2, 1.0 Hz),7.61 (1H, dd, J=12.4, 2.2 Hz), 7.73 (1H, s).

[2098] IR (Neat) cm⁻¹: 1652, 1608, 1521, 1437, 1290.

Example 242

[2099] Preparation of2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[2100] 1) Preparation of4-carboxy-2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[2101] Following the procedure of Example 1 (6),6-(3-fluoro-4-methoxyphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and3-(4-chlorophenyl)-1-propanol methanesulfonate were reacted. Withoutpurification, the reaction product was reacted further following theprocedure of Example 1 (7) to yield the title compound as a pale yellowsolid (yield: 56.1%).

[2102]¹H NMR (400 MHz, CDCl₃) δ: 2.20-2.29 (2H, m), 2.72 (2H, t, J=7.3Hz), 3.95 (3H, s), 4.37 (2H, t, J=7.3 Hz), 7.05 (1H, dd, J=8.5, 8.5 Hz),7.10 (2H, d, J=8.5 Hz), 7.22 (2H, d, J=8.5 Hz), 7.53 (1H, m), 7.63 (1H,dd, J=12.2, 2.2 Hz), 8.56 (1H, s).

[2103] 2) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-one

[2104] Following the procedure of Example 1 (8),4-carboxy-2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-3-methoxyphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as apale yellow solid (yield: 32.5%).

[2105]¹H NMR (400 MHz, CDCl₃) δ: 2.14-2.24 (2H, m), 2.69 (2H, t, J=7.6Hz), 3.33 (1H, m), 3.94 (3H, s), 4.26 (2H, t, J=7.2 Hz), 4.69 (2H, d,J=1.4 Hz), 7.01 (1H, dd, J=8.4, 8.4 Hz), 7.13 (2H, d, J=8.2 Hz), 7.22(2H, d, J=8.2 Hz), 7.49 (1H, ddd, J=8.4, 2.0, 1.2 Hz), 7.60 (1H, dd,J=12.5, 2.1 Hz), 7.65 (1H, s).

[2106] 3) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one

[2107] Following the procedure of Example 1 (9),2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-hydroxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow solid (yield:79.3%).

[2108]¹H NMR (400 MHz, CDCl₃) δ: 2.15-2.24 (2H, m), 2.70 (2H, t, J=7.3Hz), 3.17 (3H, s), 3.95 (3H, s), 4.27 (2H, t, J=6.8 Hz), 5.25 (2H, d,J=1.2 Hz), 7.03 (1H, dd, J=8.6, 8.6 Hz), 7.13 (2H, d, J=8.5 Hz), 7.23(2H, d, J=8.5 Hz), 7.49 (1H, ddd, J=8.6, 2.2, 1.2 Hz), 7.61 (1H, dd,J=12.2, 2.2 Hz), 7.72 (1H, t, J=1.2 Hz).

[2109] 4) Preparation of2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one

[2110] Following the procedure of Example 1 (10),2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted to yield the title compound as a pale yellow syrup (yield:76.9%).

[2111]¹H NMR (400 MHz, CDCl₃) δ: 2.15-2.24 (2H, m), 2.33 (3H, s),2.47-2.66 (8H, m), 2.70 (2H, t, J=7.6 Hz), 3.55 (2H, d, J=1.4 Hz), 3.95(3H, s), 4.27 (2H, t, J=7.1 Hz), 7.04 (1H, dd, J=8.8, 8.8 Hz), 7.13 (2H,d, J=8.5 Hz), 7.21 (2H, d, J=8.5 Hz), 7.49 (1H, m), 7.60 (1H, dd,J=12.4, 2.2 Hz), 7.70 (1H, s).

[2112] IR (Neat) cm⁻¹: 1652, 1608, 1521, 1437, 1282.

Example 243

[2113] Preparation of4-aminomethyl-2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[2114] Following the procedure of Example 24 (1),2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted. Without purification, the reaction product was reactedfollowing the procedure of Example 24 (2) to yield the title compound asa pale yellow syrup (yield: 48.2%).

[2115]¹H NMR (400 MHz, CDCl₃) δ: 2.17-2.27 (2H, m), 2.85 (2H, t, J=7.4Hz), 3.89 (2H, d, J=1.2 Hz), 3.94 (3H, s), 4.32 (2H, t, J=7.0 Hz), 7.02(1H, dd, J=8.6, 8.6 Hz), 7.13 (1H, ddd, J=7.6, 7.6, 2.0 Hz), 7.18 (1H,ddd, J=7.4, 7.4, 1.6 Hz), 7.27 (1H, m), 7.32 (1H, dd, J=7.6, 1.4 Hz),7.52 (1H, m), 7.62 (1H, dd, J=12.5, 2.2 Hz), 7.67 (1H, s).

[2116] IR (Neat) cm⁻¹: 1652, 1604, 1522, 1438, 1275.

Example 244

[2117] Preparation of4-aminomethyl-2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one

[2118] Following the procedure of Example 24 (1),2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-onewas reacted. Without purification, the reaction product was reactedfollowing the procedure of Example 24 (2) to yield the title compound asa pale yellow solid (yield: 48.2%).

[2119]¹H NMR (400 MHz, CDCl₃) δ: 2.14-2.26 (2H, m), 2.70 (2H, t, J=7.4Hz), 3.87 (2H, s), 3.95 (3H, s), 4.27 (2H, t, J=7.2 Hz), 7.02 (1H, dd,J=8.6, 8.6 Hz), 7.14 (2H, d, J=8.4 Hz), 7.22 (2H, d, J=8.4 Hz), 7.51(1H, d, J=8.0 Hz), 7.61 (1H, dd, J=12.5, 2.2 Hz), 7.65 (1H, s).

[2120] IR (KBr) cm⁻¹: 1652, 1604, 1522, 1438, 1275.

Example 245

[2121] Preparation of2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[2122] Following the procedure of Example 4,2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield thetitle compound as a colorless crystalline powder (yield: 91.6%).

[2123] Melting point: 235-239° C. (dec.)

[2124]¹H NMR (400 MHz, DMSO-d₆) δ: 2.75 (3H, s), 3.16-3.42 (8H, m), 3.63(2H, s), 3.90 (3H, s), 5.31 (2H, s), 7.19-7.40 (4H, m), 7.60-7.67 (2H,m), 7.87 (1H,

[2125] IR (KBr) cm⁻¹: 3439, 1652, 1605, 1519, 1441, 1290, 1139.

Example 246

[2126] Preparation of2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one hydrochloride

[2127] Following the procedure of Example 4,2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 91.1%).

[2128] Melting point: 216-218° C.

[2129]¹H NMR (400 MHz, DMSO-d₆) δ: 2.77 (6H, s), 3.91 (3H, s), 4.24 (2H,s), 5.35 (2H, s), 7.21-7.44 (4H, m), 7.66-7.74 (2H, m), 8.45 (1H, s).

[2130] IR (KBr) cm⁻¹: 3435, 1647, 1606, 1519, 1438, 1284.

Example 247

[2131] Preparation of2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-o ne dihydrochloride

[2132] Following the procedure of Example 4,2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onewas reacted to yield the title compound as a colorless crystallinepowder (yield: 50.0%).

[2133] Melting point: 244-245° C.

[2134]¹H NMR (400 MHz, DMSO-d₆) δ: 2.05-2.15 (2H, m), 2.32 (3H, s), 2.68(2H, t, J=7.8 Hz), 2.81 (3H, s), 3.20-3.60 (10H, m), 4.18 (2H, t, J=7.8Hz), 7.27 (2H, d, J=8.6 Hz), 7.29-7.39 (3H, m), 7.75 (1H, m), 7.80 (1H,m), 8.37 (1H, brs).

[2135] IR (KBr) cm⁻¹: 1650, 1607, 1493, 1241, 1158, 1016, 942, 827.

Example 248

[2136] Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-onedihydrochloride

[2137] Following the procedure of Example 4,2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one was reacted to yield thetitle compound as a colorless crystalline powder (yield: 85.2%).

[2138] Melting point: 248-250° C. (dec.)

[2139]¹H NMR (400 MHz, DMSO-d₆) δ: 2.76 (3H, s), 2.98-3.18 (4H, m),3.25-3.39 (4H, m), 3.82 (2H, s), 3.90 (3H, s), 4.92 (2H, d, J=6.4 Hz),6.46 (1H, dt, J=15.6, 6.4 Hz), 6.65 (1H, d, J=15.6 Hz), 7.25 (1H, dd,J=8.5, 8.5 Hz), 7.33 (2H, d, J=8.5 Hz), 7.44 (2H, d, J=8.5 Hz),7.65-7.73 (2H, m), 8.07 (1H, s).

[2140] IR (KBr) cm⁻¹: 2936, 1652, 1607, 1523, 1439, 1286.

Example 249

[2141] Preparation of2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-onedihydrochloride

[2142] Following the procedure of Example 4,2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one was reacted toyield the title compound as a colorless crystalline powder (yield:82.6%).

[2143] Melting point: 220-228° C. (dec.)

[2144]¹H NMR (400 MHz, DMSO-d₆) δ: 2.96-3.08 (4H, m), 3.17 (2H, t, J=5.4Hz), 3.28-3.44 (4H, m), 3.75 (2H, s), 3.79 (2H, t, J=5.1 Hz), 3.90 (3H,s), 4.92 (2H, dd, J=6.4, 1.2 Hz), 6.46 (1H, dt, J=16.1, 6.4 Hz), 6.65(1H, d, J=16.1 Hz), 7.25 (1H, dd, J=8.5, 8.5 Hz), 7.33 (2H, d, J=8.5Hz), 7.44 (2H, d, J=8.5 Hz), 7.65-7.72 (2H, m), 8.00 (1H, s).

[2145] IR (KBr) cm⁻¹: 2937, 1656, 1611, 1525, 1438, 1285.

[2146] Experiment 1

[2147] Inhibitory Activity Against Interleukin-1β Production

[2148] HL-60 cells were cultured for 4 days until confluence on RPMI1640 medium with 10% fetal bovine serum (FBS) added thereto. The mediumwas centrifuged. The supernatant was discarded, and the cells were thensuspended at 1×10⁶ cells/mL on RPMI 1640 medium with 3% FBS, andlipopolysaccharide was added to give a final concentration of 10 μg/mL.The culture was inoculated at 1 mL/well to a 24-well plate. A samplecompound was added at 1 μL/well, followed by culturing for 3 days. Threedays later, the amount of interleukin-1β in each culture was determinedby ELISA. Each IC₅₀ value was determined by a comparison in yield with acontrol to which no test sample was added. Results on somerepresentative compounds are shown in Tables 1 and 2. TABLE 1 (1)

IL-1β production Example inhibiting activity No. X Y Z n R¹ R²(R¹)N—Salt IC50 (μM) 8 Me F H 1 iso-Bu Me₂N— HCl 3.45 14 MeO F H 1 CyprCH₂Me₂N— HCl 3.61 18 MeO F H 1 CyprCH₂

2HCl 5.40 21 MeO F H 1 CyprCH₂

2HCl 1.01 23 MeO F H 1 CyprCH₂ (HOCH₂CH₂)₂N— HCl 12.33 25 MeO F H 1CyprCH₂ H₂N— HCl 2.74 45 Me H H 1 iso-Bu Me₂N— HCl 6.21 47 Me H H 1iso-Bu Et₂N— HCl 5.20 49 Me H H 1 iso-Bu (HOCH₂CH₂)₂N— HCl 3.53 83 F MeH 1 iso-Bu

2HCl 0.27 89 F Me H 1 iso-Bu Me₂N— HCl 5.50 108 F F H 1 iso-Bu(HOCH₂CH₂)₂N— HCl 3.44 143 F Me H 1

2HCl 8.55 149 MeS H H 1 CyprCH₂

2HCl 1.63 153 NeS H H 1 CyprCH₂ Me₂N— HCl 0.58 161 MeS H H 1 iso-BuMe₂N— HCl 2.78 163 MeS H H 1 iso-Bu

HCl 2.78 213 MeO F H 3 CyprCH₂

free 0.24 216 MeO F H 3 CyprCH₂ H₂N— free 1.14 189 MeO F H 1

free 0.87 192 MeO F H 1

free 0.64

[2149] TABLE 2 (1)

IL-1β production Example inhibiting activity No. X Y Z n R¹ A IC50 (μM)207 MeO F H 1

2.7 208 MeO F H 1

Me₂N— 6.1 209 MeO F H 1

2.8 210 MeO F H 1

3.1 218 F Me H 1

6.8 222 F Me H 1

5.8 227 F Me H 3

H₂N— 5.2 230 F Me H 1

4.0 231 F Me H 1

5.7 241 MeO F H 1

6.4 242 MeO F H 1

7.7

[2150] Experiment 2 (Water Solubility Test)

[2151] Testing Method

[2152] Each sample compound was weighed in the amount shown in Table 3,to which purified water was added in 0.05 mL aliquots. The solubility(%) of the compound was determined based on the amount of water requiredfor its dissolution.

[2153] Results

[2154] As is shown in Table 3, the compounds of the present inventionshowed water solubility significantly improved over the comparativecompounds. TABLE 3 Amount of Weighed amount added water SolubilityExample No. (mg) (mL) (%) 14 2.048 0.25 0.8 18 1.048 0.1 1 21 10.470.05 >20 23 10.82 0.1 10 25 1.025 0.25 0.4 45 10.37 0.25 4 47 10.470.05 >20 89 10.57 0.05 >20 108 9.75 0.045 >20 143 5.023 0.05 10 149 3.090.03 >10 153 2.95 0.6 0.5 188 2.008 2.5 0.08 193 5.032 0.1 5 195 5.0722.2 0.2 206 2.042 3.5 0.06 214 5.061 0.05 10 217 5.061 0.05 10 245 5.0200.05 10 246 4.992 0.2 2 247 4.999 0.05 10 248 2.002 3.5 0.06 249 2.0177.0 0.03 Comparative 0.677 100 <0.001 Compound 1 (insoluble) Comparative0.742 100 <0.001 Compound 2 (insoluble) Comparative 0.740 100 <0.001Compound 3 (insoluble) Comparative 0.95 100 <0.001 Compound 4(insoluble)

Comp.comp'd 1

Comp.comp'd 2

Comp.comp'd 3

Comp.comp'd 4

[2155] Experiment 3 (Oral Absorbability Test on Rats)

[2156] The compound of Example 83 and the comparative compound 3 weresuspended at 2 mg/mL with a 0.5% MC solution in mortars, respectively,and were orally administered to male SD rats at 10 mg/5 mL/kg. Uponelapsed time of 0.25, 0.5, 1, 2, 4, 6 and 8 hours after theadministration, blood samples were collected and then centrifuged toprovide plasma samples. The plasma levels of the respective compoundswere determined by HPLC. As is shown in FIG. 1, no substantialabsorption was observed on the comparative compound 3, but goodabsorption was observed on the compound of Example 83 equipped withincreased water solubility. The compound of Example 83 is, therefore,useful as an orally dosable medicine.

[2157] Experiment 4 (Oral Absorbability Test on Rats and/or Mice)

[2158] In a similar manner as in Experiment 3, test compounds ofExamples 23, 25, 143, 193, 245, 246, 247, 248 and 249 were orallyadministered to mice and/or rats to test their oral absorbability. As isshown in FIGS. 2 to 6, good absorbability was observed on all of thesetest compounds so that they are useful as orally dosable medicines.

[2159] Having described the present invention, it will now be apparentto one of ordinary skill in the art that many changes and modificationsmay be made to the above-described embodiments without departing fromthe spirit and the scope of the present invention.

1. A phenylpyridazine compound having the formula (1):

wherein: R¹ is optionally substituted alkyl, or optionally substitutedalkenyl; R² and R³ each independently represents hydrogen or an alkyl,hydroxyalkyl, dihydroxyalkyl or alkynyl, or R² and R³ are fused togetherwith the adjacent nitrogen atom to form an optionally substituted,nitrogen-containing, saturated heterocyclic group; X, Y and Z eachindependently represents hydrogen or halogen, optionally substitutedalkyl, alkoxy, alkylthio, alkylsulfinyl or alkylsulfonyl, or optionallysubstituted aryl; and n stands for a number of from 1 to 5; with theproviso that R² and R³ are not hydrogen or the same C₁-C₃ alkyl groupsat the same time when R¹ is a benzyl group or a C₁-C₃ alkyl group; or asalt thereof
 2. The compound of claim 1, wherein R¹ is optionallysubstituted alkyl having 1 to 7 carbon atoms or optionally substitutedalkenyl having 2 to 7 carbon atoms.
 3. The compound of claim 2, whereinone or more substituents on said alkyl or alkenyl group represented byR¹ are each independently an aryl group having 6 to about 14 carbonatoms or a 5- or 6-membered heteroaryl group having 1 to 3 nitrogenatoms; and said aryl or heteroaryl group are each optionally substitutedby 1 to 3 substituents selected from the group consisting of halogen,alkyl groups and alkoxy.
 4. The compound of claim 1, wherein R² and R³each independently represents hydrogen, alkyl, hydroxyalkyl,dihydroxyalkyl or alkynyl; or R² and R³ are fused together with theadjacent nitrogen atom to form a 5- or 7-membered, nitrogen-containing,saturated heterocyclic group, said heterocyclic group being optionallysubstituted with one or more halogen atoms, or alkyl, alkoxycarbonyl oraralkyl groups.
 5. The compound of claim 1, wherein X, Y and Z eachindependently are hydrogen, halogen, alkyl which is optionallysubstituted by one or more halogen atoms an alkoxy, alkylthio,alkylsulfinyl, alkylsulfonyl, or C₆-C₁₄ aryl groups which are optionallysubstituted by one or more of halogen, alkyl or alkoxy.
 6. The compoundof claim 1, wherein R¹ is isobutyl, cyclopropylmethyl,cyclopentylmethyl, cinnamyl, halogenocinnamyl, benzyl, halogenobenzyl ordihalogenobenzyl; R² and R³ are each independently hydrogen, C17 alkyl,C₁₇ hydroxyalkyl or propargyl; said heterocyclic group formed by R² andR³ is C₁₇ alkyl or is piperazinyl, piperidino or morpholino which isoptionally substituted by one or more benzyl; X is methyl, methoxy,methylthio or halogen; Y is hydrogen, methyl or halogen; Z is hydrogen;and n is 1 or
 3. 7. The compound of claim 1, which comprises4-dimethylaminomethyl-6-(3-fluoro-4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,2-cyclopropylmethyl-4-dimethylamino-methyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-benzyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-cyclopropyl-methyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)-methyl-2H-pyridazin-3-one,4-N,N-bis(2-hydroxyethyl)amino-methyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,4-dimethyl-aminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyridazin-3-one,4-diethylaminomethyl-2-isobutyl-6-(4-methylphenyl)-2H-pyrid azin-3-one,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(4-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,4-dimethylaminomethyl-6-(4-fluoro-3-methylphenyl)-2-isobutyl-2H-pyridazin-3-one,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3,4-difluorophenyl)-2-isobutyl-2H-pyridazin-3-one,2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-cyclopropylmethyl-4-(4-methyl-1-piperazinyl)methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropyl-methyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,2-cyclopropylmethyl-4-dimethylaminomethyl-6-[4-(methylthio)-phenyl]-2H-pyridazin-3-one,2-isobutyl-6-[4-(methylthio)-phenyl]-4-propargylaminomethyl-2H-pyridazin-3-one,4-dimethylaminomethyl-2-isobutyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one,2-(4-chlorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-cyclopentylmethyl-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,4-aminomethyl-2-cyclopentylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,4-dimethylaminomethyl-2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one, 4-aminomethyl-2-(4-fluorobenzyl)-6-(3fluoro-4-methoxypheny l)-2H-pyridazin-3-one,4-aminomethyl-2-(4-chlorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,4-N,N-bis(2-hydroxyethyl)aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,4-aminomethyl-6-(3-fluoro-4-methoxyphenyl)-2-[3-(4-fluorophenyl)propyl]-2H-pyridazin-3-one,2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one,2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one,2-cyclopropylmethyl-4-(3-dimethylaminopropyl)-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one, or4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one.
 8. The compound of claim 1, wherein R is agroup selected from halogenobenzyl, dihalogenobenzyl, (halogenophenyl)ethyl, (dihalogenophenyl)ethyl, (halogenophenyl)propyl or(dihalogenophenyl)propyl; R²(R³)N— is a group selected from amino,dimethylamino, piperazinyl or N-methylpiperazinyl; X is halogen ormethoxy; Y is methyl or halogen; Z is hydrogen; and n is 1 or
 3. 9. Thecompound of claim 1, wherein R¹ is a group selected from chlorobenzyl,dichlorobenzyl, fluorobenzyl, difluorobenzyl, (chlorophenyl)ethyl,(dichlorophenyl)ethyl, (chlorophenyl)propyl or (dichlorophenyl)propyl;R²(R³)N— is a group selected from amino, dimethylamino, piperazinyl orN-methylpiperazinyl; x is halogen or methoxy; Y is methyl or halogen; Zis hydrogen; and n is 1 or
 3. 10. The compound of claim 1, which is:2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-[3-(2-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-[3-(3-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one,4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,2-[2-(2-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-[2-(4-chlorophenyl)ethyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,4-aminomethyl-2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one,2-[3-(2,6-dichlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one2-(3,4-difluorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,4-aminomethyl-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one, 2-(4-fluorobenzyl)-6(3-fluoro-4-methoxyphenyl)-4-[3-(4-methyl-1-piperazinyl)propyl]-2H-pyridazin-3-one,2-(4-fluorobenzyl)-6(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,4-aminomethyl-2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,4-aminomethyl-2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one, and2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one.11. The compound of claim 1, which is2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(4-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,4-(3-aminopropyl)-2-(2-chlorobenzyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one, 2-[2-(4-chlorophenyl)ethyl]-6(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(2,6-dichlorobenzyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-[3-(2-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-[3-(4-chlorophenyl)propyl]-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,4-(3-aminopropyl)-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,2-(3,4-difluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(3,4-difluorobenzyl)-4-dimethylaminomethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one,4-N,N-bis(2-hydroxyethyl)aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one,4-aminomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one, or2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one.12. The compound of claim 1, which is2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-[3-(1-piperazinyl)propyl]-2H-pyridazin-3-one,2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-(1-piperazinyl)methyl-2H-pyridazin-3-one,2-[3-(4-chlorophenyl)propyl]-6-(4-fluoro-3-methylphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-(4-methyl-1-piperazinyl)methyl-2H-pyridazin-3-one,or2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-4-[4-(2-hydroxyethyl)-1-piperazinyl]methyl-2H-pyridazin-3-one,or a salt thereof.
 13. A medicine comprising as an active ingredient thecompound of any one of claims 1-12 or a salt thereof.
 14. The medicineof claim 13, which is a preventive or therapeutic for a disease causedby stimulation of interleukin-1β production.
 15. The medicine of claim13, which is a preventive or therapeutic for immune system diseases,inflammatory diseases, ischemic diseases, osteoporosis, or ichorrhemia.16. The medicine of claim 13, which is a preventive or therapeutic forrheumatism, arthritis or inflammatory colitis.
 17. An interleukin-1βproduction inhibitor comprising as an active ingredient the compound ofany one of claims 1-12 or a salt thereof.
 18. A pharmaceuticalcomposition comprising the compound of any one of claims 1-12 or a saltthereof and a pharmacologically acceptable carrier.
 19. Thepharmaceutical composition of claim 18, which is a pharmaceuticalcomposition for the prevention or treatment of a disease caused bystimulation of interleukin-1β production.
 20. The pharmaceuticalcomposition of claim 18, which is a pharmaceutical composition for theprevention or treatment of immune system diseases, inflammatorydiseases, ischemic diseases, osteoporosis, or ichorrhemia.
 21. Thepharmaceutical composition of claim 18, which is a pharmaceuticalcomposition for the prevention or treatment of rheumatism, arthritis orinflammatory colitis.
 22. Use of the compound of any one of claims 1-12or a salt thereof for the production of a medicine.
 23. The use of claim22, wherein said medicine is a preventive or therapeutic for a diseasecaused by stimulation of interleukin-1β production.
 24. The use of claim22, wherein said medicine is a preventive or therapeutic for immunesystem diseases, inflammatory diseases, ischemic diseases, osteoporosis,or ichorrhemia.
 25. The use of claim 22, wherein said medicine is apreventive or therapeutic for rheumatism, arthritis or inflammatorycolitis.
 26. A method for treating a disease caused by stimulation ofinterleukin-1β production, which comprises administering the compound ofany one of claims 1-12 or a salt thereof.
 27. A method for treatingimmune system diseases, inflammatory diseases, ischemic diseases,osteoporosis or ichorrhemia, which comprises administering the compoundof any one of claims 1-12 or a salt thereof.
 28. The method of claim 27,wherein rheumatism, arthritis or inflammatory colitis is treated.